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Wang H, Gong F, Zhao W, Huang Y, Zhou C, Wang J. Melatonin Inhibiting Neuronal Cells Ferroptosis Through Lipid Metabolic Reprogramming. Mol Neurobiol 2025:10.1007/s12035-025-05035-9. [PMID: 40366559 DOI: 10.1007/s12035-025-05035-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/02/2025] [Indexed: 05/15/2025]
Abstract
This study aims to identify the underlying mechanism by which melatonin protects neurons. Firstly, the inhibitory effect of melatonin on ferroptosis was verified by treating HT22 cells with melatonin, Erastin, and Ferrostatin-1. Secondly, transcriptomic and metabolomic analyses were performed. Melatonin-related hub genes were identified by differential gene expression analysis, and lipid metabolism-related critical signaling pathways and biological processes (BPs) were determined by gene set enrichment analysis (GSEA). Finally, the expression of hub genes was verified by quantitative real-time PCR (qRT-PCR) or Western Blot (WB), and the involvement of Tribble 3 (Trib3) in the regulation of lipid metabolism and ferroptosis by melatonin was confirmed by Cell Counting Kit 8 (CCK-8) assay, ROS analysis, and WB. Assay results showed that melatonin significantly increased Gpx4 activity, decreased ROS generation, and inhibited ferroptosis in HT22 cells. The hub gene Trib3 was obtained by transcriptomic analysis, and its expression was upregulated with Erastin treatment. Lipid metabolomic analysis suggested that the regulation of lipid metabolism by melatonin was associated with glycerophospholipids. In vitro experiments showed that Trib3 was regulated by the upstream factor Atf4, and the protein levels of Trib3 and Atf4 were significantly increased after Erastin treatment. However, melatonin can reduce the protein levels of Trib3 and Atf4, increase the survival rate of HT-22 cells and the activity of GPX4, and reduce the ROS content. Melatonin inhibits neuronal ferroptosis by affecting the Atf4/Trib3 axis via the modulation of lipid metabolism.
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Affiliation(s)
- Haifeng Wang
- Department of Neurosurgery, Ningbo Key Laboratory of Neurological Diseases and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang Province, China.
| | - Fanyong Gong
- Department of Neurosurgery, Ningbo Key Laboratory of Neurological Diseases and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang Province, China
| | - Wenhui Zhao
- Psychosomatic Medical Center, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang Province, China.
| | - Yi Huang
- Department of Neurosurgery, Ningbo Key Laboratory of Neurological Diseases and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang Province, China
| | - Chenhui Zhou
- Department of Neurosurgery, Ningbo Key Laboratory of Neurological Diseases and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang Province, China
| | - Jianyong Wang
- Department of Neurosurgery, Ningbo Key Laboratory of Neurological Diseases and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang Province, China
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Karasu N, Kuzucu M, Mat OC, Gul M, Yay A, Dundar M. Protective effect of deinoxanthin in sorafenib-induced nephrotoxicity in rats with the hepatocellular carcinoma model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:5969-5988. [PMID: 39625488 DOI: 10.1007/s00210-024-03633-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/13/2024] [Indexed: 04/11/2025]
Abstract
Sorafenib is a synthetic compound and an orally administered multichines inhibitor that targets growth signaling and angiogenesis. It is widely recognized as the standard of care for advanced hepatocellular carcinoma (HCC) but has toxic side effects. Deinoxanthin, purified from the radioresistant bacterium Deinococcus radiodurans, has strong antioxidant characteristics. In this study, the protective effect of deinoxanthin against sorafenib-induced nephrotoxicity was investigated in a rat model of hepatocellular carcinoma. In this regard, the expressions of DDAH1, KIM1, and INOS genes were examined, histopathological and immunohistochemical analyses were performed, and various parameters such as SOD, MDA, GST, CAT, TAS, and TOS were tested biochemically. BUN and creatinine levels were measured in renal tissues. RT-qPCR, Western blot, and ELISA methods were used for all these analyses. As a result, the analyses show that deinoxanthin, which has a high antioxidant capacity, reduces kidney injury and can be used as a protective agent. The primary objective of this study is to evaluate the potential of deinoxanthin as a protective agent against the nephrotoxic side effects of sorafenib in HCC. Our study identified the potential synergistic effects of sorafenib and deinoxanthin on nephrotoxicity in rats with hepatocellular carcinoma.
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Affiliation(s)
- Nilgun Karasu
- Faculty of Medicine, Department of Medical Genetics, Erciyes University, Kayseri, Turkey
- Faculty of Medicine, Department of Medical Genetics, Uskudar University, Istanbul, Turkey
| | - Mehmet Kuzucu
- Faculty of Arts and Sciences, Department of Biology, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Ozge Cengiz Mat
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Mustafa Gul
- Faculty of Medicine, Department of Physiology, Ataturk University, Erzurum, Turkey
| | - Arzu Yay
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Munis Dundar
- Faculty of Medicine, Department of Medical Genetics, Erciyes University, Kayseri, Turkey.
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Yousefi T, Yousef Memar M, Ahmadi Jazi A, Zand S, Reiter RJ, Amirkhanlou S, Mostafa Mir S. Molecular pathways and biological roles of melatonin and vitamin D; effects on immune system and oxidative stress. Int Immunopharmacol 2024; 143:113548. [PMID: 39488920 DOI: 10.1016/j.intimp.2024.113548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/27/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024]
Abstract
Melatonin and vitamin D are associated with the immune system and have important functions as antioxidants. Numerous attempts have been made to identify up to date activities of these molecules in various physiological conditions. The biosynthetic pathways of melatonin and vitamin D are correlated to sun exposure in an inverse manner. Vitamin D is biosynthesized when the skin is exposed to the sun's UV radiation, while melatonin synthesis occurs in the pineal gland principally during night. Additionally, vitamin D is particularly associated with intestinal absorption, metabolism, and homeostasis of ions including calcium, magnesium. However, melatonin has biological marks and impacts on the sleep-wake cycle. The roles of vitamin D and melatonin are opposed to each other individually, but either of them is implicated in the immune system. Recently studies have shown that melatonin and vitamin D have their specific set of aberrations in different cell signaling pathways, such as serine/threonine-specific protein kinase (Akt), phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and Notch. The aim of this review is to clarify the common biological functions and molecular mechanisms through which melatonin and vitamin D could deal with different signaling pathways.
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Affiliation(s)
- Tooba Yousefi
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Iran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirreza Ahmadi Jazi
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shahabedin Zand
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, Long School of Medicine, San Antonio, TX, USA
| | - Saeid Amirkhanlou
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran; Department of Nephrology, Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Mostafa Mir
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Iran.
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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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de Almeida Chuffa LG, Seiva FRF, Silveira HS, Cesário RC, da Silva Tonon K, Simão VA, Zuccari DAPC, Reiter RJ. Melatonin regulates endoplasmic reticulum stress in diverse pathophysiological contexts: A comprehensive mechanistic review. J Cell Physiol 2024; 239:e31383. [PMID: 39039752 DOI: 10.1002/jcp.31383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/13/2024] [Accepted: 07/05/2024] [Indexed: 07/24/2024]
Abstract
The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin's therapeutic potential in these conditions.
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Affiliation(s)
- Luiz Gustavo de Almeida Chuffa
- Department of Structural and Functional Biology, Institute of Bioscences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Fábio Rodrigues Ferreira Seiva
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Henrique S Silveira
- Department of Structural and Functional Biology, Institute of Bioscences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Roberta Carvalho Cesário
- Department of Structural and Functional Biology, Institute of Bioscences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Karolina da Silva Tonon
- Department of Structural and Functional Biology, Institute of Bioscences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Vinicius Augusto Simão
- Department of Structural and Functional Biology, Institute of Bioscences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Debora Aparecida P C Zuccari
- Department of Molecular Biology, Faculty of Medicine of São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UTHealth, San Antonio, Texas, USA
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Liu D, Shan M, Zeng R, He M, Dai X, Lu L, Yang M, He H, Zhang Y, Xiang L, Chen A, Sun L, He F, Lian J. Inhibition of KIAA1429/HK1 axis enhances the sensitivity of liver cancer cells to sorafenib by regulating the Warburg effect. Biochem Pharmacol 2024; 227:116419. [PMID: 38996929 DOI: 10.1016/j.bcp.2024.116419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/06/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
N6-methyladenosine (m6A) serves as the most abundant posttranscription modification. However, the role of m6A in tumorigenesis and chemotherapeutic drugs sensitivity remains largely unclear. Present research focuses on the potential function of the m6A writer KIAA1429 in tumor development and sorafenib sensitivity in liver cancer. We found that the level of KIAA1429 was significantly elevated in liver cancer tissues and cells and was closely associated with poorer prognosis. Functionally, KIAA1429 promoted the proliferation and Warburg effect of liver cancer cells in vitro and in vivo. RNA-seq and MeRIP-seq analysis revealed the glycolysis was one of the most affected pathways by KIAA1429, and m6A-modified HK1 was the most likely targeted gene to regulate the Warburg effect. KIAA1429 depletion decreased Warburg effect and increased sorafenib sensitivity in liver cancer. Mechanistically, KIAA1429 could affect the m6A level of HK1 mRNA through directly binding with it. Moreover, KIAA1429 cooperated with the m6A reader HuR to enhance HK1 mRNA stability, thereby upregulating its expression. These findings demonstrated that KIAA1429/HK1 axis decreases the sensitivity of liver cancer cells to sorafenib by regulating the Warburg effect, which may provide a novel therapeutic target for liver cancer treatment.
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Affiliation(s)
- Dong Liu
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - Meihua Shan
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - Rong Zeng
- Department of Medicinal Chemistry, Army Medical University, Chongqing 400038, China
| | - Meng He
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing 400038, China
| | - Xufang Dai
- College of Education Science, Chongqing Normal University, Chongqing 400047, China
| | - Lu Lu
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - Mingzhen Yang
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - Haiyan He
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing 400038, China
| | - Yang Zhang
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - Li Xiang
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - An Chen
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China
| | - Liangbo Sun
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China.
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing 400038, China.
| | - Jiqin Lian
- Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China.
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Alhasan B, Gladova YA, Sverchinsky DV, Aksenov ND, Margulis BA, Guzhova IV. Hsp70 Negatively Regulates Autophagy via Governing AMPK Activation, and Dual Hsp70-Autophagy Inhibition Induces Synergetic Cell Death in NSCLC Cells. Int J Mol Sci 2024; 25:9090. [PMID: 39201776 PMCID: PMC11354248 DOI: 10.3390/ijms25169090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
Proteostasis mechanisms, such as proteotoxic-stress response and autophagy, are increasingly recognized for their roles in influencing various cancer hallmarks such as tumorigenesis, drug resistance, and recurrence. However, the precise mechanisms underlying their coordination remain not fully elucidated. The aim of this study is to investigate the molecular interplay between Hsp70 and autophagy in lung adenocarcinoma cells and elucidate its impact on the outcomes of anticancer therapies in vitro. For this purpose, we utilized the human lung adenocarcinoma A549 cell line and genetically modified it by knockdown of Hsp70 or HSF1, and the H1299 cell line with knockdown or overexpression of Hsp70. In addition, several treatments were employed, including treatment with Hsp70 inhibitors (VER-155008 and JG-98), HSF1 activator ML-346, or autophagy modulators (SAR405 and Rapamycin). Using immunoblotting, we found that Hsp70 negatively regulates autophagy by directly influencing AMPK activation, uncovering a novel regulatory mechanism of autophagy by Hsp70. Genetic or chemical Hsp70 overexpression was associated with the suppression of AMPK and autophagy. Conversely, the inhibition of Hsp70, genetically or chemically, resulted in the upregulation of AMPK-mediated autophagy. We further investigated whether Hsp70 suppression-mediated autophagy exhibits pro-survival- or pro-death-inducing effects via MTT test, colony formation, CellTiter-Glo 3D-Spheroid viability assay, and Annexin/PI apoptosis assay. Our results show that combined inhibition of Hsp70 and autophagy, along with cisplatin treatment, synergistically reduces tumor cell metabolic activity, growth, and viability in 2D and 3D tumor cell models. These cytotoxic effects were exerted by substantially potentiating apoptosis, while activating autophagy via rapamycin slightly rescued tumor cells from apoptosis. Therefore, our findings demonstrate that the combined inhibition of Hsp70 and autophagy represents a novel and promising therapeutic approach that may disrupt the capacity of refractory tumor cells to withstand conventional therapies in NSCLC.
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Affiliation(s)
- Bashar Alhasan
- Lab of Cell Protection Mechanisms, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (Y.A.G.); (D.V.S.); (N.D.A.); (B.A.M.); (I.V.G.)
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Wang J, Su Q, Chen K, Wu Q, Ren J, Tang W, Hu Y, Zhu Z, Cheng C, Tu K, He H, Zhang Y. Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma. J Pharm Anal 2024; 14:211-224. [PMID: 38464783 PMCID: PMC10921246 DOI: 10.1016/j.jpha.2023.05.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/13/2023] [Accepted: 05/29/2023] [Indexed: 03/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.
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Affiliation(s)
- Jingjing Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Qi Su
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Kun Chen
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Qing Wu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jiayan Ren
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wenjuan Tang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yu Hu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Zeren Zhu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Cheng Cheng
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Kaihui Tu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Huaizhen He
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
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Chen YM, Yang WQ, Gu CW, Fan YY, Liu YZ, Zhao BS. Amlodipine inhibits the proliferation and migration of esophageal carcinoma cells through the induction of endoplasmic reticulum stress. World J Gastroenterol 2024; 30:367-380. [PMID: 38313237 PMCID: PMC10835542 DOI: 10.3748/wjg.v30.i4.367] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 12/21/2023] [Accepted: 01/03/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND L-type calcium channels are the only protein channels sensitive to calcium channel blockers, and are expressed in various cancer types. The Cancer Genome Atlas database shows that the mRNA levels of multiple L-type calcium channel subunits in esophageal squamous cell carcinoma tumor tissue are significantly higher than those in normal esophageal epithelial tissue. Therefore, we hypothesized that amlodipine, a long-acting dihydropyridine L-type calcium channel blocker, may inhibit the occurrence and development of esophageal cancer (EC). AIM To investigate the inhibitory effects of amlodipine on EC through endoplasmic reticulum (ER) stress. METHODS Cav1.3 protein expression levels in 50 pairs of EC tissues and corresponding paracancerous tissues were examined. Subsequently, the inhibitory effects of amlodipine on proliferation and migration of EC cells in vitro were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and Transwell assays. In vivo experiments were performed using murine xenograft model. To elucidate the underlying mechanisms, in vitro cell studies were performed to confirm that ER stress plays a role in inhibition proliferation and migration of EC cells treated with amlodipine. RESULTS The expression level of Cav1.3 in esophageal carcinoma was 1.6 times higher than that in paracancerous tissues. Amlodipine treatment decreased the viability of esophageal carcinoma cells in a dose- and time-dependent manner. In vivo animal experiments also clearly indicated that amlodipine inhibited the growth of EC tumors in mice. Additionally, amlodipine reduces the migration of tumor cells by inhibiting epithelial-mesenchymal transition (EMT). Mechanistic studies have demonstrated that amlodipine induces ER stress-mediated apoptosis and suppresses EMT. Moreover, amlodipine-induced autophagy was characterized by an increase in autophagy lysosomes and the accumulation of light chain 3B protein. The combination of amlodipine with the ER stress inhibitor 4-phenylbutyric acid further confirmed the role of the ER stress response in amlodipine-induced apoptosis, EMT, and autophagy. Furthermore, blocking autophagy increases the ratio of apoptosis and migration. CONCLUSION Collectively, we demonstrate for the first time that amlodipine promotes apoptosis, induces autophagy, and inhibits migration through ER stress, thereby exerting anti-tumor effects in EC.
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Affiliation(s)
- Yan-Min Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Department of Oncology, The Affiliated Hospital, Henan Polytechnic University, Jiaozuo 454000, Henan Province, China
| | - Wen-Qian Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Cheng-Wei Gu
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Ying-Ying Fan
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Yu-Zhen Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
- Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
| | - Bao-Sheng Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
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Gao J, Hou Y, Yang X, Liu J, Zhang Y. Melatonin enhances the sensitivity of colorectal cancer cells to 5-fluorouracil through the regulation of the miR-532-3p/β-catenin pathway. ENVIRONMENTAL TOXICOLOGY 2024; 39:367-376. [PMID: 37755321 DOI: 10.1002/tox.23978] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/04/2023] [Accepted: 09/18/2023] [Indexed: 09/28/2023]
Abstract
This research aimed to investigate whether melatonin affected sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) as well as to show the underlying molecular mechanism. Melatonin and 5-FU were added to CRC cells at varying doses. The effect of melatonin on sensitivity to 5-FU was investigated by measuring cell activity and apoptosis, and the potential underlying mechanism was further explored by detecting miR-532-3p expression and the associated pathway proteins. Melatonin could suppress cell malignancy in SW480 and HCT116 cells. Melatonin also significantly promoted sensitivity to 5-FU in CRC cells. miR-532-3p expression was downregulated in CRC and was also markedly enhanced when treated with 1 mmol/L melatonin. The inhibitory ability of the co-cultured melatonin, 5-FU, and miR-532-3p inhibitor on SW480 and HCT116 cells was markedly diminished, and the IC50 value was significantly enhanced. Relative to the melatonin group, melatonin+miR-532-3p inhibitor markedly declined apoptosis rate. Bioinformatics analysis predicted the target of miR-532-3p. β-catenin level presented obvious downregulation in the melatonin group, while it was notably upregulated in the co-culture group in relative to with that in the melatonin group. Overall, melatonin promotes sensitivity to 5-FU in CRC cells by regulating the miR-532-3p/β-catenin pathway.
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Affiliation(s)
- Jun Gao
- Department of Pharmacy, The People's Hospital of Henan University of Chinese Medicine (the People's Hospital of Zhengzhou), Zhengzhou, China
| | - Yi Hou
- Department of Pharmacy, The Seventh People's Hospital of Zhengzhou, Zhengzhou, China
| | - Xiaorui Yang
- Department of Clinical Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Jia Liu
- Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Ying Zhang
- Department of Clinical Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
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11
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Chen S, Dai M. The miR-224-5p/SIRT3/AMPK/mTOR axis is involved in the melatonin-mediated inhibition of glucocorticoid-induced osteoporosis by activating autophagy. Hum Cell 2023; 36:1965-1977. [PMID: 37486565 DOI: 10.1007/s13577-023-00929-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 06/02/2023] [Indexed: 07/25/2023]
Abstract
Melatonin has been shown to exert an inhibitory effect on osteoporosis. This study investigates the function of the miR-224-5p/SIRT3/AMPK/mTOR axis in melatonin-mediated effects against osteoporosis. Human bone marrow mesenchymal stem cells (hBMSCs) were treated with glucocorticoid dexamethasone to induce an in vitro osteoporosis model. After melatonin treatment, miR-224-5p and SIRT3 levels were measured by RT‒PCR. Transmission electron microscopy and immunofluorescence were conducted for evaluating autophagy. Western blotting was carried out to determine the expression of osteogenesis-related proteins (Runx2, OSX, OPN, and OCN), SIRT3-AMPK-mTOR axis, and autophagy-related markers (LC3 and p62). Alizarin red staining was used to measure matrix mineralization. The data showed that melatonin inhibited dexamethasone-induced osteoporosis in vitro, and enhanced autophagic levels (as indicated by increased LC3 puncta, LC3II/I ratio, and autophagic vacuoles). In terms of the mechanisms, melatonin decreased miR-224-5p expression and increased SIRT3. SRIT3 was shown to be a direct target of miR-224-5p. miR-224-5p upregulation or SIRT3 downregulation reversed the effects of melatonin on osteoporosis and suppressed autophagy. Additionally, miR-224-5p inhibited SIRT3 expression and AMPK pathway activation. In summary, we discovered that melatonin suppressed glucocorticoid-induced osteoporosis and autophagy inhibition via the miR-224-5p/SIRT3/AMPK/mTOR axis.
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Affiliation(s)
- Sheng Chen
- Department of Orthopedic, Shaoxing Second Hospital, No.123 Yan'an Road, Shaoxing, 312000, Zhejiang, China
| | - Min Dai
- Department of Orthopedic, The First Affiliated Hospital of Nanchang University, No.17 Yongwai Zheng Street, Donghu District, Nanchang, 330006, Jiangxi, China.
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12
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Cheng Q, Liu K, Xiao J, Shen K, Wang Y, Zhou X, Wang J, Xu Z, Yang L. SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop. J Exp Clin Cancer Res 2023; 42:232. [PMID: 37670384 PMCID: PMC10478313 DOI: 10.1186/s13046-023-02807-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/22/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND Sec23 homolog A (SEC23A), a core component of coat protein complex II (COPII), has been reported to be involved in several cancers. However, the role of SEC23A in gastric cancer remains unclear. METHODS The expression of SEC23A in gastric cancer was analyzed by using qRT-PCR, western blotting and IHC staining. The role of SEC23A in ER stress resistance was explored by functional experiments in vitro and vivo. The occupation of STAT3 on the SEC23A promoter region was verified by luciferase reporter plasmids and CHIP assay. The interaction between SEC23A and ANXA2 was identified by Co-IP and mass spectrometry analysis. RESULTS We demonstrated that SEC23A was upregulated in gastric cancer and predicted poor prognosis in patients with gastric cancer. Mechanistically, SEC23A was transcriptional upregulated by ER stress-induced pY705-STAT3. Highly expressed SEC23A promoted autophagy by regulating the cellular localization of ANXA2. The SEC23A-ANXA2-autophay axis, in turn, protected gastric cancer cells from ER stress-induced apoptosis. Furthermore, we identified SEC23A attenuated 5-FU therapeutic effectiveness in gastric cancer cells through autophagy-mediated ER stress relief. CONCLUSION We reveal an ER stress-SEC23A-autophagy negative feedback loop that enhances the ability of gastric cancer cells to resist the adverse survival environments. These results identify SEC23A as a promising molecular target for potential therapeutic intervention and prognostic prediction in patients with gastric cancer.
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Affiliation(s)
- Quan Cheng
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Kanghui Liu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Jian Xiao
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Kuan Shen
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Yuanhang Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Xinyi Zhou
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Jiawei Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Zekuan Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Li Yang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China.
- Department of General Surgery, Liyang People's Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Liyang, Jiangsu Province, China.
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13
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Ferrell JM. Circadian rhythms and inflammatory diseases of the liver and gut. LIVER RESEARCH 2023; 7:196-206. [PMID: 39958387 PMCID: PMC11791922 DOI: 10.1016/j.livres.2023.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/24/2023] [Accepted: 08/14/2023] [Indexed: 01/03/2025]
Abstract
Circadian rhythms play a central role in maintaining metabolic homeostasis and orchestrating inter-organ crosstalk. Research evidence indicates that disruption to rhythms, which occurs through shift work, chronic sleep disruption, molecular clock polymorphisms, or the consumption of alcohol or high-fat diets, can influence inflammatory status and disrupt timing between the brain and periphery or between the body and the external environment. Within the liver and gut, circadian rhythms direct the timing of glucose and lipid homeostasis, bile acid and xenobiotic metabolism, and nutrient absorption, making these systems particularly susceptible to the effects of disrupted rhythms. In this review, the impacts of circadian disruption will be discussed with emphasis on inflammatory conditions affecting the liver and gut, and the potential for chronotherapy for these conditions will be explored.
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Affiliation(s)
- Jessica M. Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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14
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Ragusa MA, Naselli F, Cruciata I, Volpes S, Schimmenti C, Serio G, Mauro M, Librizzi M, Luparello C, Chiarelli R, La Rosa C, Lauria A, Gentile C, Caradonna F. Indicaxanthin Induces Autophagy in Intestinal Epithelial Cancer Cells by Epigenetic Mechanisms Involving DNA Methylation. Nutrients 2023; 15:3495. [PMID: 37571432 PMCID: PMC10420994 DOI: 10.3390/nu15153495] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Autophagy is an evolutionarily conserved process critical in maintaining cellular homeostasis. Recently, the anticancer potential of autophagy inducers, including phytochemicals, was suggested. Indicaxanthin is a betalain pigment found in prickly pear fruit with antiproliferative and pro-apoptotic activities in colorectal cancer cells associated with epigenetic changes in selected methylation-silenced oncosuppressor genes. Here, we demonstrate that indicaxanthin induces the up-regulation of the autophagic markers LC3-II and Beclin1, and increases autophagolysosome production in Caco-2 cells. Methylomic studies showed that the indicaxanthin-induced pro-autophagic activity was associated with epigenetic changes. In addition to acting as a hypermethylating agent at the genomic level, indicaxanthin also induced significant differential methylation in 39 out of 47 autophagy-related genes, particularly those involved in the late stages of autophagy. Furthermore, in silico molecular modelling studies suggested a direct interaction of indicaxanthin with Bcl-2, which, in turn, influenced the function of Beclin1, a key autophagy regulator. External effectors, including food components, may modulate the epigenetic signature of cancer cells. This study demonstrates, for the first time, the pro-autophagic potential of indicaxanthin in human colorectal cancer cells associated with epigenetic changes and contributes to outlining its potential healthy effect in the pathophysiology of the gastrointestinal tract.
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Affiliation(s)
- Maria Antonietta Ragusa
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Flores Naselli
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Ilenia Cruciata
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Sara Volpes
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Chiara Schimmenti
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Graziella Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Maurizio Mauro
- Department of Obstetrics & Gynecology and Women’s Health, Michael F. Price Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Mariangela Librizzi
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Claudio Luparello
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
- NBFC—National Biodiversity Future Center, 90133 Palermo, Italy
| | - Roberto Chiarelli
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Chiara La Rosa
- Department of Life Sciences and Systems Biology, Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10124 Turin, Italy;
| | - Antonino Lauria
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Carla Gentile
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
| | - Fabio Caradonna
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; (M.A.R.); (F.N.); (I.C.); (S.V.); (C.S.); (G.S.); (M.L.); (C.L.); (R.C.); (A.L.); (F.C.)
- NBFC—National Biodiversity Future Center, 90133 Palermo, Italy
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15
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Wang H, Wang Y, Li J, He Z, Boswell SA, Chung M, You F, Han S. Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes. BMC Med 2023; 21:147. [PMID: 37069550 PMCID: PMC10108821 DOI: 10.1186/s12916-023-02838-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 03/17/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. METHODS Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. RESULTS Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. CONCLUSIONS Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity.
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Affiliation(s)
- Huan Wang
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
| | - Yiming Wang
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Jiongyuan Li
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Ziyi He
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Sarah A Boswell
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Mirra Chung
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Fuping You
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Sen Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China
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16
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Hashemi M, Mirzaei S, Zandieh MA, Rezaei S, Amirabbas Kakavand, Dehghanpour A, Esmaeili N, Ghahremanzade A, Saebfar H, Heidari H, Salimimoghadam S, Taheriazam A, Entezari M, Ahn KS. Long non-coding RNAs (lncRNAs) in hepatocellular carcinoma progression: Biological functions and new therapeutic targets. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:207-228. [PMID: 36584761 DOI: 10.1016/j.pbiomolbio.2022.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/29/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Liver is an important organ in body that performs vital functions such as detoxification. Liver is susceptible to development of cancers, and hepatocellular carcinoma (HCC) is among them. 75-85% of liver cancer cases are related to HCC. Therefore, much attention has been directed towards understanding factors mediating HCC progression. LncRNAs are epigenetic factors with more than 200 nucleotides in length located in both nucleus and cytoplasm and they are promising candidates in cancer therapy. Directing studies towards understanding function of lncRNAs in HCC is of importance. LncRNAs regulate cell cycle progression and growth of HCC cells, and they can also induce/inhibit apoptosis in tumor cells. LncRNAs affect invasion and metastasis in HCC mainly by epithelial-mesenchymal transition (EMT) mechanism. Revealing the association between lncRNAs and downstream signaling pathways in HCC is discussed in the current manuscript. Infectious diseases can affect lncRNA expression in mediating HCC development and then, altered expression level of lncRNA is associated with drug resistance and radio-resistance. Biomarker application of lncRNAs and their role in prognosis and diagnosis of HCC are also discussed to pave the way for treatment of HCC patients.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Sahar Rezaei
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Negin Esmaeili
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Azin Ghahremanzade
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Hajar Heidari
- Department of Biomedical Sciences, School of Public Health University at Albany State University of New York, Albany, NY, 12208, USA
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
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17
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Ngai ZN, Chok KC, Ng KY, Koh RY, Chye SM. Potential role of melatonin in prevention and treatment of lung cancer. Horm Mol Biol Clin Investig 2022; 43:485-503. [PMID: 35728260 DOI: 10.1515/hmbci-2022-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022]
Abstract
Lung cancer is the second most common cancer and the most lethal cancer worldwide. Melatonin, an indoleamine produced in the pineal gland, shows anticancer effects on a variety of cancers, especially lung cancer. Herein, we clarify the pathophysiology of lung cancer, the association of circadian rhythm with lung, and the relationship between shift work and the incidence of lung cancer. Special focus is placed on the role of melatonin receptors in lung cancer, the relationship between inflammation and lung cancer, control of cell proliferation, apoptosis, autophagy, and immunomodulation in lung cancer by melatonin. A review of the drug synergy of melatonin with other anticancer drugs suggests its usefulness in combination therapy. In summary, the information compiled may serve as a comprehensive reference for the various mechanisms of action of melatonin against lung cancer, as a guide for the design of future experimental research and for advancing melatonin as a therapeutic agent for lung cancer.
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Affiliation(s)
- Zi Ni Ngai
- School of Health Science, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Kian Chung Chok
- School of Health Science, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Khuen Yen Ng
- School of Pharmacy, Monash University Malaysia, Subang Jaya, Selangor, Malaysia
| | - Rhun Yian Koh
- Division of Applied Biomedical Science and Biotechnology, School of Health Science, International Medical University, Kuala Lumpur, Malaysia
| | - Soi Moi Chye
- Division of Applied Biomedical Science and Biotechnology, School of Health Science, International Medical University, Kuala Lumpur, Malaysia
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18
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Gómez-Sierra T, Jiménez-Uribe AP, Ortega-Lozano AJ, Ramírez-Magaña KJ, Pedraza-Chaverri J. Antioxidants affect endoplasmic reticulum stress-related diseases. VITAMINS AND HORMONES 2022; 121:169-196. [PMID: 36707134 DOI: 10.1016/bs.vh.2022.10.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
The endoplasmic reticulum (ER) is a complex multifunctional organelle that maintains cell homeostasis. Intrinsic and extrinsic factors alter ER functions, including the rate of protein folding that triggers the accumulation of misfolded proteins and alters homeostasis, thus generating stress in the ER, which activates the unfolded protein response (UPR) pathway to promote cell survival and restore their homeostasis; however, if the damage is not corrected, it could also trigger cell death. In addition, ER stress and oxidative stress are closely related because excessive production of reactive oxygen species (ROS), a well-known inducer of ER stress, promotes the accumulation of misfolded proteins; at the same time, the ER stress enhances ROS production, generating a pathological cycle. Furthermore, it has been described that the dysregulation of the UPR contributes to the progression of various diseases, so the use of compounds capable of regulating ER stress, such as antioxidants, has been used in several experimental models of diseases to alleviate the damage induced by the maladaptive signaling of the UPR, the mechanism of action of antioxidants generally is dose-dependent, and it is specific in each tissue and pathology, could decrease or enhance specific proteins of the UPR to have beneficial or detrimental effects.
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Affiliation(s)
- Tania Gómez-Sierra
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Alexis Paulina Jiménez-Uribe
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Ariadna Jazmín Ortega-Lozano
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Karla Jaqueline Ramírez-Magaña
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - José Pedraza-Chaverri
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico.
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19
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Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy. Cells 2022; 11:cells11233773. [PMID: 36497032 PMCID: PMC9738281 DOI: 10.3390/cells11233773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.
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Stępniak J, Krawczyk-Lipiec J, Lewiński A, Karbownik-Lewińska M. Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid. Biomedicines 2022; 10:biomedicines10112890. [PMID: 36428458 PMCID: PMC9687109 DOI: 10.3390/biomedicines10112890] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022] Open
Abstract
Sorafenib and lenvatinib are multi-targeted tyrosine kinase inhibitors which are currently approved to treat advanced hepatocellular carcinoma, renal cell carcinoma and radioiodine-refractory differentiated thyroid carcinoma. However this treatment is often limited due to common adverse events which may occur via oxidative stress. The study aims to compare sorafenib- and lenvatinib-induced oxidative damage to membrane lipids (lipid peroxidation, LPO) in homogenates of porcine noncancerous tissues of the thyroid, the liver, and the kidney and to check if it can be prevented by antioxidants melatonin and indole-3-propionic acid (IPA). Homogenates of individual tissues were incubated in the presence of sorafenib or lenvatinib (1 mM, 100 µM, 10 µM, 1 µM, 100 nM, 10 nM, 1 nM, 100 pM) together with/without melatonin (5.0 mM) or IPA (5.0 mM). The concentration of malondialdehyde + 4-hydroxyalkenals, as the LPO index, was measured spectrophotometrically. The incubation of tissue homogenates with sorafenib resulted in a concentration-dependent increase in LPO (statistically significant for concentrations of 1mM and 100 µM in the thyroid and the liver, and of 1 mM, 100 µM, and 10 µM in the kidney). The incubation of thyroid homogenates with lenvatinib did not change LPO level. In case of the liver and the kidney, lenvatinib increased LPO but only in its highest concentration of 1 mM. Melatonin and IPA reduced completely (to the level of control) sorafenib- and lenvatinib-induced LPO in all examined tissues regardless of the drug concentration. In conclusion, sorafenib comparing to lenvatinib is a stronger damaging agent of membrane lipids in noncancerous tissues of the thyroid, the liver, and the kidney. The antioxidants melatonin and IPA can be considered to be used in co-treatment with sorafenib and lenvatinib to prevent their undesirable toxicity occurring via oxidative stress.
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Affiliation(s)
- Jan Stępniak
- Department of Oncological Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland
| | - Joanna Krawczyk-Lipiec
- Department of Oncological Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland
| | - Andrzej Lewiński
- Polish Mother’s Memorial Hospital—Research Institute, 93-338 Lodz, Poland
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, 93-338 Lodz, Poland
| | - Małgorzata Karbownik-Lewińska
- Department of Oncological Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland
- Polish Mother’s Memorial Hospital—Research Institute, 93-338 Lodz, Poland
- Correspondence:
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21
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Pavlović N, Heindryckx F. Targeting ER stress in the hepatic tumor microenvironment. FEBS J 2022; 289:7163-7176. [PMID: 34331743 DOI: 10.1111/febs.16145] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/30/2021] [Indexed: 01/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer.
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Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala University, Sweden
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22
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Moon B, Park M, Cho SH, Kim KM, Seo HR, Kim JH, Kim JA. Synergistic antitumor activity of sorafenib and MG149 in hepatocellular carcinoma cells. BMB Rep 2022; 55. [PMID: 35880431 PMCID: PMC9623241 DOI: 10.5483/bmbrep.2022.55.10.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress. [BMB Reports 2022; 55(10): 506-511].
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Affiliation(s)
- Byul Moon
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113, Korea,Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Mijin Park
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113, Korea,Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Seung-Hyun Cho
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113, Korea,Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Haeng Ran Seo
- Advanced Biomedical Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Korea
| | - Jeong-Hoon Kim
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113, Korea,Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea,Corresponding authors. Jeong-Hoon Kim, Tel: +82-42-860-4264; Fax: +82-42-860-4598; E-mail: ; Jung-Ae Kim, Tel: +82-42-879-8129; Fax: +82-42-879-8119; E-mail: jungaekim@ kribb.re.kr
| | - Jung-Ae Kim
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon 34113, Korea,Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea,Corresponding authors. Jeong-Hoon Kim, Tel: +82-42-860-4264; Fax: +82-42-860-4598; E-mail: ; Jung-Ae Kim, Tel: +82-42-879-8129; Fax: +82-42-879-8119; E-mail: jungaekim@ kribb.re.kr
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23
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Aslankoc R, Savran M, Doğuç DK, Sevimli M, Tekin H, Kaynak M. Ameliorating effects of ramelteon on oxidative stress, inflammation, apoptosis, and autophagy markers in methotrexate-induced cerebral toxicity. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:1183-1189. [PMID: 36311194 PMCID: PMC9588322 DOI: 10.22038/ijbms.2022.62955.13913] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 08/30/2022] [Indexed: 11/20/2022]
Abstract
Objectives Methotrexate (MTX) is a widely used chemotherapeutic agent that, however, is known to have serious side effects such as neurotoxicity. In the present study, we aimed to evaluate the possible favorable effects of ramelteon (RMLT) on MTX-induced cerebral toxicity. Materials and Methods Thirty-two male Wistar albino rats were divided into four groups: Control group, MTX group (20 mg/kg MTX, IP, single dose), MTX+RMLT group (20 mg/kg MTX, IP, single dose + 10 mg/kg RMLT, by gavage, 7 days), and RMLT group (10 mg/kg RMLT, by gavage, 7 days). Results In the MTX group, increased levels of total oxidant status (TOS) and oxidative stress index (OSI) levels and decreased levels of total antioxidant status (TAS) level were observed. RMLT significantly reversed oxidative stress parameters. Real-time PCR analysis revealed that MTX increased the expressions of Beclin-1 and autophagy-related gene 12 (ATG12). These expressions were significantly decreased by RMLT. Vacuolar changes, apoptotic cells, and inflammatory cell infiltration induced by MTX were ameliorated by RMLT treatment. Increased tumor necrosis factor-α (TNF- α) and Caspase-3 activities induced by MTX were returned to their normal levels by RMLT. Conclusion All our results demonstrate that RMLT alleviates the harmful effects of MTX on the cerebral cortex tissue. Therefore, RMLT may be considered for supportive therapy for preventing side effects of MTX in patients needing MTX therapy.
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Affiliation(s)
- Rahime Aslankoc
- Süleyman Demirel University, Faculty of Medicine, Department of Physiology, Isparta, Turkey,Corresponding author: Rahime Aslankoc. Süleyman Demirel University, Faculty of Medicine, Department of Physiology 32260 Isparta, Turkey. Tel: +90-2462113606; Fax: +902462371165;
| | - Mehtap Savran
- Süleyman Demirel University, Faculty of Medicine, Department of Pharmacology, Isparta, Turkey
| | - Duygu Kumbul Doğuç
- Süleyman Demirel University, Faculty of Medicine, Department of Biochemistry, Isparta, Turkey
| | - Murat Sevimli
- Süleyman Demirel University, Faculty of Medicine, Department of Histology and Embryology, Isparta, Turkey
| | - Hale Tekin
- Süleyman Demirel University, Graduate School of Natural and Applied Sciences, Department of Bioengineering, Isparta, Turkey
| | - Mine Kaynak
- Süleyman Demirel University, Faculty of Medicine, Department of Pharmacology, Isparta, Turkey
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24
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Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma. J Immunol Res 2022; 2022:1366508. [PMID: 36003068 PMCID: PMC9393196 DOI: 10.1155/2022/1366508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/29/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) with cancer cells under endoplasmic reticulum (ER) stress has a poor prognosis. This study is aimed at discovering credible biomarkers for predicting the prognosis of HCC based on ER stress-related genes (ERSRGs). We constructed a novel four-ERSRG prognostic risk model, including PON1, AGR2, SSR2, and TMCC1, through a series of bioinformatic approaches, which can accurately predict survival outcomes in HCC patients. Higher risk scores were linked to later grade, recurrence, advanced TNM stage, later T stage, and HBV infection. In addition, 20 fresh frozen tumors and normal tissues from HCC patients were collected and used to validate the genes expressed in the signature by qRT-PCR and immunohistochemical (IHC) assays. Moreover, we found the ER stress-related signature could reflect the infiltration levels of different immune cells in the tumor microenvironment (TME) and forecast the efficacy of immune checkpoint inhibitor (ICI) treatment. Finally, we created a nomogram incorporating this ER stress-related signature. In conclusion, our constructed four-gene risk model associated with ER stress can accurately predict survival outcomes in HCC patients, and the model's risk score is associated with the poor clinical classification.
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25
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Sun Y, Guan X, Zhang T, Li Y, Shi H, Chitakunye AT, Hong H, Zhang S, Zhu Q, Cai L. Regulation of the sensitivity of hepatocarcinoma cells by ORMDL3, to sorafenib by autophagy. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:159. [PMID: 35972600 PMCID: PMC9381447 DOI: 10.1007/s12032-022-01767-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/10/2022] [Indexed: 12/24/2022]
Abstract
Serum orosomucoid1-like protein 3 (ORMDL3) is a membrane protein in the endoplasmic reticulum, known to regulate many important signal transduction processes and autophagy regulation, but it is unclear whether it is involved in the intratumoral microenvironment and cancer drug resistance. Our present study found that silencing ORMDL3 increases the inhibitory effect of sorafenib on the viability and proliferation in HCC cells, and increases the sensitivity of HCC cells to sorafenib. In addition, silencing ORMDL3 can increase ROS levels by inhibiting autophagy, thereby increasing sorafenib-induced apoptosis of HCC cells. Further, our study also found that ORMDL3 silencing inhibits autophagy through the PERK-ATF4-Beclin1 pathway, thus affecting sorafenib sensitivity. The in vivo effects of sorafenib were tested by xenografting using nude mice. It showed that silencing ORMDL3 in HCC cells could increase the inhibitory effect of sorafenib on the growth of tumors. This is the first report to describe the relationships among ORMDL3, autophagy, and sorafenib resistance. This study provides available targets that might have a synergetic effect with sorafenib.
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Affiliation(s)
- Yixiao Sun
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Xueran Guan
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Ting Zhang
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Yue Li
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Huiling Shi
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Ashleigh Tinotenda Chitakunye
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Hanyu Hong
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Shihui Zhang
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Qin Zhu
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China
| | - Lin Cai
- Department of Biopharmaceuticals, School of Pharmaceutics Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang Province, China.
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Lyu X, Zeng L, Shi J, Ming Z, Li W, Liu B, Chen Y, Yuan B, Sun R, Yuan J, Zhao N, Yang X, Chen G, Yang S. Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib. J Exp Clin Cancer Res 2022; 41:200. [PMID: 35690866 PMCID: PMC9188165 DOI: 10.1186/s13046-022-02390-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/15/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. METHODS The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. RESULTS Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. CONCLUSIONS Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment.
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Affiliation(s)
- Xin Lyu
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Lizhong Zeng
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Jie Shi
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Zongjuan Ming
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Wei Li
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Boxuan Liu
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Yang Chen
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Bo Yuan
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Ruiying Sun
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Jingyan Yuan
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Nannan Zhao
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Xia Yang
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
| | - Guoan Chen
- School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District, Shenzhen, 518055 Guangdong China
| | - Shuanying Yang
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi’an, 710004 Shaanxi People’s Republic of China
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Hu JM, Chang YL, Hsieh CC, Huang SM. The Synergistic Cytotoxic Effects of GW5074 and Sorafenib by Impacting Mitochondrial Functions in Human Colorectal Cancer Cell Lines. Front Oncol 2022; 12:925653. [PMID: 35747833 PMCID: PMC9209736 DOI: 10.3389/fonc.2022.925653] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) ranks third in the United States for incidence or mortality. Surgical resection is the primary treatment for patients at an early stage, while patients with advanced and metastatic CRC receive combined treatment with chemotherapy, radiotherapy, or targeted therapy. C-RAF plays a key role in maintaining clonogenic and tumorigenic capacity in CRC cells and it might be a potential therapeutic target for CRC. Sorafenib is a popular oral multi-kinase inhibitor, including a B-RAF inhibitor that targets the RAF-MEK-ERK pathway. Sorafenib, as a single agent, has tumor-suppressing efficacy, but its clinical application is limited due to many complex drug resistance mechanisms and side effects. GW5074 is one of the C-RAF inhibitors and has the potential to enhance the efficacy of existing cancer chemotherapies. In this study, we investigated whether the combination of sorafenib with GW5074 could reduce the dosage of sorafenib and enhance its tumor-suppressive effect in two CRC cell lines, HCT116 and LoVo cells. Our findings demonstrate that GW5074 can potentiate the cytotoxicity of sorafenib and dramatically reduce the half-maximal inhibitory concentration (IC50) dose of sorafenib from 17 and 31 µM to 0.14 and 0.01 µM in HCT116 and LoVo cells, respectively. GW5074, similar to sorafenib, suppressed the cellular proliferation and induced cellular apoptosis and cytosolic ROS, but had no further enhancement on the above-mentioned effects when combined with sorafenib. The synergistic effects of GW5074 and sorafenib were mainly found in mitochondrial functions, including ROS generation, membrane potential disruption, and fission–fusion dynamics, which were examined by using the flow cytometry analysis. In summary, the C-RAF inhibitor GW5074 might potentiate the cytotoxicity of the B-RAF inhibitor sorafenib mediated through mitochondrial dysfunctions, suggesting that GW5074 potentially serves as a sensitizer for sorafenib application to reduce the risk of drug resistance of CRC treatment. Our findings also provide novel insights on using C-RAF inhibitors combined with sorafenib, the current CRC therapeutic drug choice, in CRC treatment.
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Affiliation(s)
- Je-Ming Hu
- Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Department of Surgery, Division of Colorectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yung-Lung Chang
- Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Chih Hsieh
- School of Pharmacy and Institute of Pharmacy, National Defense Medical Center, Taipei, Taiwan
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Shih-Ming Huang
- Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
- *Correspondence: Shih-Ming Huang,
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Wang A, Zhou B, Zhu Y, Tan C, Xu J, Cui J, Zhang L, Sun G. Melatonin Reduces Apoptosis Resistance of Hepatocellular Carcinoma Cells by Inhibiting BMAL1. Integr Cancer Ther 2022. [PMCID: PMC9178991 DOI: 10.1177/15347354221099539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Purpose: This study aimed to explore the role and molecular mechanism of brain and muscle ARNT-like protein 1 (BMAL1) in hepatocellular carcinoma (HCC), and the effect of melatonin on BMAL1 expression and apoptosis of HCC cells. Methods: We mainly used immunohistochemistry, western blot, cck-8 assays, flow cytometry, wound-healing assay, transwell assay, and RT-qPCR for this research. Results: The expression of BMAL1 protein was frequently up-regulated in the tissues and cell lines of HCC patients. Its high expression was significantly associated with tumor size, tumor differentiation degree, and shorter survival. In addition, cell functional experiments showed that BMAL1 could promote proliferation and migration, and inhibit apoptosis in HCC cell lines. Furthermore, the expression of BMAL1 was related to the endoplasmic reticulum stress (ERS) level. Knockdown of BMAL1 could inhibit the expression of ERS-related protein, while overexpression of BMAL1 led to the increase of ERS-related protein’s level. Low concentration of ERS led to the increase of BMAL1, and a certain degree of ERS in turn inhibited the expression of BMAL1. Melatonin promoted apoptosis of hepatoma cells by inhibiting the expression of BMAL1. Conclusion: BMAL1 plays a key role in HCC patients’ survival and tumor growth, which may be related to its interaction with ERS-related pathways. Melatonin can regulate ERS-related apoptosis resistance by inhibiting BMAL1 expression, promoting apoptosis of HCC cells.
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Affiliation(s)
- Anqi Wang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Bei Zhou
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yue Zhu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chaisheng Tan
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jing Xu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jie Cui
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Li Zhang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guoping Sun
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Guo B, Xu X, Shao M, Yang X, He G, Qi K, Gu J, Wang L. UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response. Biochem Biophys Res Commun 2022; 613:207-213. [PMID: 35617808 DOI: 10.1016/j.bbrc.2022.05.048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 02/06/2023]
Abstract
As the first-generation targeted therapy, sorafenib remains an effective single-drug treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, the existence of resistance restricts the long-term benefit of patients. UDP-glucose 6-dehydrogenase (UGDH) is the key enzyme of glucuronic acid metabolism which was largely reported in mediating drug systemic elimination. In this study, we explore its critical role in regulating sorafenib sensitivity. Here we find sorafenib exposure could activate glucuronic acid metabolism, accompanied with the elevated expression of UGDH. Interference with the route by silencing UGDH could boost HCC cells sensitivity to sorafenib. Meanwhile, the analysis of HCC patients with sorafenib treatment displayed that low UGDH expression predicted superior prognosis. Further screening assay suggested that unfolded protein response (UPR) involves in UGDH silencing-mediated apoptosis. Xenograft model confirmed that combined UGDH intervention could significantly improve sorafenib efficacy. Our results reveal the impact of sorafenib exposure on glucuronic acid metabolism reprogramming and provide UGDH as a promising target to improve sorafenib efficacy.
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Affiliation(s)
- Bao Guo
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Xiaoyan Xu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Core Facility Center, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Miaomiao Shao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xu Yang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Gaofei He
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Kangwei Qi
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jianxin Gu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Lan Wang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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Zhong J, Lu S, Jia X, Li Q, Liu L, Xie P, Wang G, Lu M, Gao W, Zhao T, Wang Q, Su W, Li N. Role of endoplasmic reticulum stress in apoptosis induced by HK2 inhibitor and its potential as a new drug combination strategy. Cell Stress Chaperones 2022; 27:273-283. [PMID: 35355227 PMCID: PMC9106785 DOI: 10.1007/s12192-022-01267-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/08/2022] [Accepted: 03/22/2022] [Indexed: 01/23/2023] Open
Abstract
Compared with normal cells, tumor cells mainly obtain energy through aerobic glycolysis. Hexokinase 2 (HK2) plays a key role in the regulation of tumor cell aerobic glycolysis, and targeting HK2 has become a new strategy for cancer treatment. However, little is known about the role of HK2 in colon cancer and the regulation of its targeted inhibitors. In this study, we found that the expression of HK2 in colorectal cancer tissues was significantly higher than that in adjacent tissues, and the expression level of HK2 in metastatic colorectal cancer was further increased. Meanwhile, the expression level of HK2 was closely related to clinical TNM stage and outcome of colorectal cancer patients. We provide here evidence that HK2 inhibitor 3-Bromopyruvate acid (3-BP) can significantly inhibit the survival and proliferation of colon cancer cells, and induce apoptosis through mitochondrial apoptosis signaling pathway. In addition, we found that 3-BP can also induce endoplasmic reticulum stress in colon cancer cells, the mechanism may be through the increase of intracellular calcium concentration. In vitro and in vivo experiments showed that inhibition of endoplasmic reticulum stress could further increase the proliferation inhibition and apoptosis induced by 3-BP. Collectively, our results show that HK2 is highly expressed in colorectal cancer. 3-BP, an inhibitor of HK2, can induce apoptosis and endoplasmic reticulum stress in colon cancer cells. Endoplasmic reticulum stress plays a protective role in cell death induced by 3-BP. This result suggested that targeting HK2 and endoplasmic reticulum stress may be a valuable strategy in targeted and combination therapy of colon cancer.
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Affiliation(s)
- Jiateng Zhong
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
- Department of Gynecology, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, Henan, China.
| | - Shuya Lu
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Xiaoling Jia
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Qian Li
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Lei Liu
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Pei Xie
- Department of Gynecology, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, Henan, China
| | - Guodong Wang
- Nursing School, Xinxiang Medical University, Xinxiang, China
| | - Manman Lu
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Wuji Gao
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Tiesuo Zhao
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Qianqing Wang
- Department of Gynecology, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, Henan, China
| | - Wei Su
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
| | - Na Li
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
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Cinnamaldehyde induces autophagy-mediated cell death through ER stress and epigenetic modification in gastric cancer cells. Acta Pharmacol Sin 2022; 43:712-723. [PMID: 33980998 PMCID: PMC8888591 DOI: 10.1038/s41401-021-00672-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/28/2021] [Indexed: 02/06/2023]
Abstract
Previous reports suggested that cinnamaldehyde (CA), the bioactive ingredient in Cinnamomum cassia, can suppress tumor growth, migratory, and invasive abilities. However, the role and molecular mechanisms of CA in GC are not completely understood. In the present study, we found that CA-induced ER stress and cell death via the PERK-CHOP axis and Ca2+ release in GC cells. Inhibition of ER stress using specific-siRNA blocked CA-induced cell death. Interestingly, CA treatment resulted in autophagic cell death by inducing Beclin-1, ATG5, and LC3B expression and by inhibiting p62 expression whereas autophagy inhibition suppressed CA-induced cell death. We showed that CA induces the inhibition of G9a and the activation of LC3B. Moreover, CA inhibited G9a binding on Beclin-1 and LC3B promoter. Overall, these results suggested that CA regulates the PERK-CHOP signaling, and G9a inhibition activates autophagic cell death via ER stress in GC cells.
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Wu D, Zhang Y, Tang H, Yang J, Li M, Liu H, Li Q. [Melatonin inhibits growth and metastasis of MDA-MB-231 breast cancer cells by activating autophagy]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:278-285. [PMID: 35365454 DOI: 10.12122/j.issn.1673-4254.2022.02.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the effects of melatonin on the growth and metastasis of MDA-MB-231 breast cancer cells and explore the mechanism. METHODS MDA-MB-231 cells were treated with 1, 3 or 5 mmol/L melatonin, and the changes in cell proliferation were examined using CCK-8 assay. Colony-forming assay and wound healing assay were used to assess the effects of melatonin treatmnent on colony-forming ability and migration of the cells. Flow cytometry and immunofluoresnce assay were employed to examine apoptosis and positive staining for autophagy-related proteins in the cells treated with 3 mmol/L melatonin. The effects of melatonin treatment alone or in combination with 3-methyladenine (3-MA) on the expressions of the proteins associated with autophagy (LC3, P62 and Beclin1), apoptosis (Bcl2 and Bax) and epithelial-mesenchymal transition (E-cadherin and Snail) were examined with Western blotting. RESULTS Melatonin treatment significantly inhibited the proliferation of breast cancer cells in a concentration- and time-dependent manner (P < 0.05), suppressed colony-forming ability and migration (P < 0.01), and promoted apoptosis of the cells (P < 0.01). Melatonin treatment alone significantly increased the expressions of Bax (P < 0.05), E-cadherin, LC3-II/LC3-I, and Beclin1 and lowered the expressions of Bcl2 (P < 0.05), Snail, P62 (P < 0.05), and Bcl2/Bax ratio (P < 0.01) in the cells, and caused enhanced positive staining of Beclin1 protein and attenuated staining of P62 protein. Compared with melatonin treatment alone, melatonin treatment combined with 3-MA significantly decreased the expressions of Beclin1 (P < 0.001), LC3-II/LC3-I (P < 0.05), Bax (P < 0.01), and E-cadherin (P < 0.001) and increased the expressions of Bcl2 (P < 0.05), Snail, and Bcl2/Bax ratio (P < 0.01). CONCLUSION Melatonin can induce autophagy of MDA-MB-231 breast cancer cells to inhibit cell proliferation and metastasis and promote cell apoptosis, and suppressing autophagy can weaken the inhibitory effect of melatonin on the growth and metastasis of breast cancer cells.
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Affiliation(s)
- D Wu
- Department of Clinical Biochemistry, School of Medical Laboratory Science, Guiyang 550004, China
| | - Y Zhang
- Department of Clinical Biochemistry, School of Medical Laboratory Science, Guiyang 550004, China
| | - H Tang
- Department of Clinical Biochemistry, School of Medical Laboratory Science, Guiyang 550004, China
| | - J Yang
- Department of Clinical Biochemistry, School of Medical Laboratory Science, Guiyang 550004, China
| | - M Li
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - H Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100000, China
| | - Q Li
- Department of Clinical Biochemistry, School of Medical Laboratory Science, Guiyang 550004, China.,Guizhou Provincial Prenatal Diagnosis Center, Guiyang 550004, China
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Li X, Su S, Ye D, Yu Z, Lu W, Liu L. Hsa_circ_0020850 promotes the malignant behaviors of lung adenocarcinoma by regulating miR-326/BECN1 axis. World J Surg Oncol 2022; 20:13. [PMID: 35012553 PMCID: PMC8750879 DOI: 10.1186/s12957-021-02480-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 12/17/2021] [Indexed: 11/10/2022] Open
Abstract
Background Circular RNAs (circRNAs) are a novel type of endogenous RNAs and play vital roles in lung adenocarcinoma. However, the function and underlying mechanism of circ_0020850 in lung adenocarcinoma remain unknown. Methods The levels of circ_0020850, microRNA-326 (miR-326), and Beclin1 (BECN1) were analyzed by real-time quantitative polymerase chain reaction and western blot analyses. The migration and invasion were determined by wound healing and transwell assays, respectively. Colony formation assay was used to assess cell proliferation ability. The angiogenic ability was analyzed by Matrigel angiogenesis assay. The apoptosis rate was calculated by flow cytometry assay. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were conducted to confirm the interaction relationship among circ_0020850, miR-326, and BECN1. A xenograft mice model was established to assess the role of circ_0020850 in vivo. Results We found that circ_0020850 was obviously overexpressed in lung adenocarcinoma tissues and cells. Knockdown of circ_0020850 inhibited migration, invasion, proliferation, and angiogenesis but induced apoptosis in lung adenocarcinoma cells in vitro, as well as curbed tumor growth in vivo. MiR-326 was a target of circ_0020850, and knockdown of miR-326 abolished the suppression effect of circ_0020850 on the malignant behaviors of lung adenocarcinoma cells. Additionally, miR-326 could negatively regulate BECN1 expression, thereby regulating lung adenocarcinoma cell phenotypes. Importantly, circ_0020850 could directly bind to miR-326 and thus relieve miR-326-mediated inhibition on BECN1. Conclusion Circ_0020850 promoted the malignant development of lung adenocarcinoma by regulating miR-326/BECN1 axis, indicating that circ_0020850 might serve as a promising target for the diagnosis and treatment of lung adenocarcinoma patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-021-02480-3.
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Affiliation(s)
- Xiaoju Li
- Department of Oncology, Xiantao First People's Hospital of Yangtze University, No. 29, Middle Section of Mianzhou Avenue, Xiantao, 433000, Hubei Province, People's Republic of China
| | - Shengtian Su
- Department of Oncology, Xiantao First People's Hospital of Yangtze University, No. 29, Middle Section of Mianzhou Avenue, Xiantao, 433000, Hubei Province, People's Republic of China
| | - Dan Ye
- Department of Oncology, Xiantao First People's Hospital of Yangtze University, No. 29, Middle Section of Mianzhou Avenue, Xiantao, 433000, Hubei Province, People's Republic of China
| | - Zhigao Yu
- Department of Oncology, Xiantao First People's Hospital of Yangtze University, No. 29, Middle Section of Mianzhou Avenue, Xiantao, 433000, Hubei Province, People's Republic of China
| | - Wenjing Lu
- Department of Oncology, Xiantao First People's Hospital of Yangtze University, No. 29, Middle Section of Mianzhou Avenue, Xiantao, 433000, Hubei Province, People's Republic of China
| | - Liang Liu
- Department of Oncology, Xiantao First People's Hospital of Yangtze University, No. 29, Middle Section of Mianzhou Avenue, Xiantao, 433000, Hubei Province, People's Republic of China.
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Melatonin Attenuates Ropivacaine-Induced Apoptosis by Inhibiting Excessive Mitophagy Through the Parkin/PINK1 Pathway in PC12 and HT22 Cells. Inflammation 2022; 45:725-738. [PMID: 34994877 DOI: 10.1007/s10753-021-01579-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/07/2021] [Indexed: 11/05/2022]
Abstract
Melatonin, as an endogenous circadian indoleamine secreted by the pineal gland, executes extensive biological functions, including antioxidant, anti-inflammatory, anti-tumor, and neuroprotective effects. Although melatonin has been reported to serve as a potential therapeutic against many nerve injury diseases, its effect on ropivacaine-induced neurotoxicity remains obscure. Our research aimed to explore the impact and mechanism of melatonin on ropivacaine-induced neurotoxicity. Our results showed that melatonin pretreatment protected the cell viability, morphology, and apoptosis of PC12 and HT22 cells, and it also improved ropivacaine-induced mitochondrial dysfunction and the activation of mitophagy. In addition, we found that autophagy activation with rapamycin significantly weakened the protective effect of melatonin against ropivacaine-induced apoptosis, whereas autophagy inhibition with 3-MA enhanced the effect of melatonin. We also detected the activation of Parkin and PINK1, a canonical mechanism for mitophagy regulation, and results shown that melatonin downregulated the expression of Parkin and PINK1, and upregulated Tomm20 and COXIV proteins, so that those results indicated that melatonin protected ropivacaine-induced apoptosis through suppressing excessive mitophagy by inhibiting the Parkin/PINK1 pathway. Melatonin may be a useful potential therapeutic agent against ropivacaine-induced neurotoxicity.
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Zhang L, Li C, Fu L, Yu Z, Xu G, Zhou J, Shen M, Feng Z, Zhu H, Xie T, Zhou L, Zhou X. Protection of catalpol against triptolide-induced hepatotoxicity by inhibiting excessive autophagy via the PERK-ATF4-CHOP pathway. PeerJ 2022; 10:e12759. [PMID: 35036109 PMCID: PMC8742543 DOI: 10.7717/peerj.12759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/16/2021] [Indexed: 01/07/2023] Open
Abstract
Catalpol significantly reduces triptolide-induced hepatotoxicity, which is closely related to autophagy. The aim of this study was to explore the unclear protective mechanism of catalpol against triptolide. The detoxification effect of catalpol on triptolide was investigated in HepaRG cell line. The detoxification effects were assessed by measuring cell viability, autophagy, and apoptosis, as well as the endoplasmic reticulum stress protein and mRNA expression levels. We found that 5-20 µg/L triptolide treatments increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), as well as the expression of autophagy proteins including LC3 and Beclin1. The expression of P62 was downregulated and the production of autophagosomes was increased, as determined by transmission electron microscope and monodansylcadaverine staining. In contrast, 40 µg/L catalpol reversed these triptolide-induced changes in the liver function index, autophagy level, and apoptotic protein expression, including Cleaved-caspase3 and Cleaved-caspase9 by inhibiting excessive autophagy. Simultaneously, catalpol reversed endoplasmic reticulum stress, including the expression of PERK, which regulates autophagy. Moreover, we used the PERK inhibitor GSK2656157 to prove that the PERK-ATF4-CHOP pathway of the unfolded protein response is an important pathway that could induce autophagy. Catalpol inhibited excessive autophagy by suppressing the PERK pathway. Altogether, catalpol protects against triptolide-induced hepatotoxicity by inhibiting excessive autophagy via the PERK-ATF4-CHOP pathway. The results of this study are beneficial to clarify the detoxification mechanism of catalpol against triptolide-induced hepatotoxicity and to promote the application of triptolide.
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Affiliation(s)
- Linluo Zhang
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Changqing Li
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Ling Fu
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China,Department of Second Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Zhichao Yu
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Gengrui Xu
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Jie Zhou
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Meiyu Shen
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Zhe Feng
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Huaxu Zhu
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Tong Xie
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Lingling Zhou
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Xueping Zhou
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
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Dai Z, Wang X, Peng R, Zhang B, Han Q, Lin J, Wang J, Lin J, Jiang M, Liu H, Lee TH, Lu KP, Zheng M. Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma. Cancer Lett 2022; 524:161-171. [PMID: 34687791 DOI: 10.1016/j.canlet.2021.10.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/24/2021] [Accepted: 10/17/2021] [Indexed: 12/24/2022]
Abstract
Sorafenib and its derivative regorafenib are the first- and second-line targeted drugs for advanced HCC, respectively. Although both drugs improve overall survival, drug resistance remains the major barrier to their full efficacy. Thus, strategies to enhance sorafenib and regorafenib efficacy against HCC are solely needed. Interleukin-6 receptor alpha (IL-6Rα) is the receptor of IL-6, a multi-functional cytokine, which plays key roles in liver-regeneration, inflammation and development of hepatocellular carcinoma (HCC). Here we show the expression of IL-6Rα was induced in response to sorafenib. Depletion of IL-6Rα abolished IL-6 induced STAT3 phosphorylation at 705th tyrosine and tumor growth of HCC cells under sorafenib treatment. Mechanistically, activating transcription factor 3 (ATF3) was induced in response to sorafenib and subsequently bound to the promoter of IL-6Rα, leading to its transcriptional activation. Depletion of ATF3 or its upstream transcription factor, ATF4, attenuated IL-6Rα induction and IL-6 mediated sorafenib resistance. The ATF4-ATF3-IL-6Rα cascade is also activated by regorafenib. Furthermore, blockade of IL-6Rα with the FDA approved IL-6Rα antibody drug, Sarilumab, drastically attenuated both sorafenib and regorafenib resistance in patient-derived xenograft (PDX) tumors, where human IL-6 could be detected by a novel in situ hybridization technique, named RNAscope. Together, our data reveal that ATF3-mediated IL-6Rα up-regulation promotes both sorafenib and regorafenib resistance in HCC, and targeting IL-6Rα represents a novel therapeutic strategy to enhance sorafenib/regorafenib efficacy for advanced HCC treatment.
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Affiliation(s)
- Zichan Dai
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Xiaohan Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Rangxin Peng
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Binghui Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Qi Han
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Jie Lin
- Shengli Clinical Medical College, Fujian Medical University & Department of Pathology, Fujian Provincial Hospital, Fujian, PR China
| | - Jichuang Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Junjin Lin
- Public Technology Service Center, Fujian Medical University, Fujian, PR China
| | - Mingting Jiang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Hekun Liu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Tae Ho Lee
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Kun Ping Lu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Min Zheng
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China; Department of Biochemistry and Molecular Biology, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China.
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Zhou B, Lu D, Wang A, Cui J, Zhang L, Li J, Fan L, Wei W, Liu J, Sun G. Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:1051-1065. [PMID: 34786210 PMCID: PMC8569435 DOI: 10.1016/j.omtn.2021.09.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 07/22/2021] [Accepted: 09/24/2021] [Indexed: 01/27/2023]
Abstract
Emerging evidence has shown that endoplasmic reticulum (ER) stress promotes sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanisms are poorly understood. The purpose of this study was to explore the mechanism by which ER stress promotes sorafenib resistance in HCC. We found that pyruvate kinase isoform M2 (PKM2) was highly expressed in human HCC tissues and co-related with worse clinicopathologic features and overall survival. Activation of ER stress positively correlated with PKM2 expression both in HCC tissue samples and tunicamycin (TM)-induced HCC cell lines. PKM2 knockdown increased sorafenib-induced apoptosis and decreased the ability of colony formation, while upregulation of PKM2 reverses this phenomenon. Furthermore, high-throughput sequencing identified that activation of ER stress significantly downregulated the expression of miR-188-5p in HCC cells. According to bioinformatics analysis and dual-luciferase assays, we further confirmed that hnRNPA2B1 is the target gene of miR-188-5p. Downregulating the expression of hnRNPA2B1 with siRNA could decrease the expression of PKM2 and enhance sorafenib-induced apoptosis in HepG2 cells. Our study demonstrated that ER stress could promote sorafenib resistance through upregulating PKM2 via miR-188-5p/hnRNPA2B1. Therefore, targeting the miR-188-5p/hnRNPA2B1/PKM2 pathway and ER stress may prove instrumental in overcoming sorafenib resistance in HCC treatment.
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Affiliation(s)
- Bei Zhou
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Donghui Lu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Anqi Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Jie Cui
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Li Zhang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Jian Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Lulu Fan
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, Anhui, China
| | - Jiatao Liu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.,Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Guoping Sun
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
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The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4044606. [PMID: 34697563 PMCID: PMC8541861 DOI: 10.1155/2021/4044606] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 09/07/2021] [Accepted: 09/25/2021] [Indexed: 12/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.
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Bastani S, Akbarzadeh M, Rastgar Rezaei Y, Farzane A, Nouri M, Mollapour Sisakht M, Fattahi A, Akbarzadeh M, Reiter RJ. Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved. Int J Mol Sci 2021; 22:10874. [PMID: 34639215 PMCID: PMC8509383 DOI: 10.3390/ijms221910874] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 12/27/2022] Open
Abstract
Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.
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Affiliation(s)
- Sepideh Bastani
- Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz 51368, Iran;
- Stem Cell And Regenerative Medicine Institute (SCARM), Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Moloud Akbarzadeh
- Stem Cell And Regenerative Medicine Institute (SCARM), Tabriz University of Medical Sciences, Tabriz 51368, Iran;
- Department of Cellular and Molecular Biology, Faculty of Biological Science, Azarbaijan Shahid Madani University, Tabriz 51368, Iran
| | - Yeganeh Rastgar Rezaei
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Ali Farzane
- Department of Health Information Management, School of Allied Medical Science, Tehran University of Medical Sciences, Tehran 11369, Iran;
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
| | - Mahsa Mollapour Sisakht
- Stem Cell and Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran 11369, Iran;
- Department of Biochemistry, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - Amir Fattahi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 51368, Iran;
- Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander University of Erlangen–Nürnberg, Comprehensive Cancer Center ER-EMN, 91054 Erlangen, Germany
| | - Maryam Akbarzadeh
- Department of Biochemistry, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health, Long School of Medicine, San Antonio, TX 78229, USA;
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Endoplasmic reticulum stress: Multiple regulatory roles in hepatocellular carcinoma. Biomed Pharmacother 2021; 142:112005. [PMID: 34426262 DOI: 10.1016/j.biopha.2021.112005] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/25/2021] [Accepted: 08/01/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Endoplasmic reticulum (ER) stress is a basic cellular stress response that maintains cellular protein homeostasis under endogenous or exogenous stimuli, which depends on the stimulus, its intensity, and action time. The ER produces a corresponding cascade reaction for crosstalk of adaptive and/or pro-death regulation with other organelles. Hepatocellular carcinoma(HCC) is one of the most common malignant solid tumors with an extremely poor prognosis. Viral hepatitis infection, cirrhosis, and steatohepatitis are closely related to the occurrence and development of HCC, and ER stress has gradually been shown to be a major mechanism. Moreover, an increasing need for protein and lipid products and relative deficiencies of oxygen and nutrients for rapid proliferation and endoplasmic reticulum stress are undoubtedly involved. Therefore, to fully and comprehensively understand the regulatory role of endoplasmic reticulum stress in the occurrence and progression of HCC is of vital importance to explore its pathogenesis and develop novel anti-cancer strategies. METHODOLOGY We searched for relevant publications in the PubMed databases using the keywords "Endoplasmic reticulum stress", "hepatocellular carcinoma" in last five years,and present an overview of the current knowledge that links ER stress and HCC, which includes carcinogenesis, progression, and anti-cancer strategies, and propose directions of future research. RESULT ER stress were confirmed to be multiple regulators or effectors of cancer, which also be confirmed to drive tumorigenesis and progression of HCC. Targeting ER stress signaling pathway and related molecules could play a critical role for anti-HCC and has become a research hotspot for anti-cancer in recent years. CONCLUSION ER stress are critical for the processes of the tumorigenesis and progression of tumors. For HCC, ER stress was associated with tumorigenesis, development, metastasis, angiogenesis and drug resistance, targeting ER stress has emerged as a potential anti-tumor strategy.
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Li Y, Gao S, Du X, Ji J, Xi Y, Zhai G. Advances in autophagy as a target in the treatment of tumours. J Drug Target 2021; 30:166-187. [PMID: 34319838 DOI: 10.1080/1061186x.2021.1961792] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Autophagy is a multi-step lysosomal degradation process, which regulates energy and material metabolism and has been used to maintain homeostasis. Autophagy has been shown to be involved in the regulation of health and disease. But at present, there is no consensus on the relationship between autophagy and tumour, and we consider that it plays a dual role in the occurrence and development of tumour. That is to say, under certain conditions, it can inhibit the occurrence of tumour, but it can also promote the process of tumour. Therefore, autophagy could be used as a target for tumour treatment. The regulation of autophagy plays a synergistic role in the radiotherapy, chemotherapy, phototherapy and immunotherapy of tumour, and nano drug delivery system provides a promising strategy for improving the efficacy of autophagy regulation. This review summarised the progress in the regulatory pathways and factors of autophagy as well as nanoformulations as carriers for the delivery of autophagy modulators.
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Affiliation(s)
- Yingying Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Shan Gao
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xiyou Du
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Jianbo Ji
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Yanwei Xi
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Guangxi Zhai
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
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Huotan Jiedu Tongluo Decoction Inhibits Balloon-Injury-Induced Carotid Artery Intimal Hyperplasia in the Rat through the PERK-eIF2 α-ATF4 Pathway and Autophagy Mediation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5536237. [PMID: 34335815 PMCID: PMC8318774 DOI: 10.1155/2021/5536237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/07/2021] [Accepted: 07/10/2021] [Indexed: 11/18/2022]
Abstract
In-stent restenosis (ISR) is the main factor affecting the outcome of percutaneous coronary intervention (PCI), and its main pathological feature is neointimal hyperplasia. Huotan Jiedu Tongluo decoction (HTJDTLD) is an effective traditional Chinese medicine (TCM) prescription for the treatment of vascular stenosis diseases. However, the precise anti-ISR mechanism of HTJDTLD remains unclear. Here, we investigated whether HTJDTLD can inhibit the excessive activation of endoplasmic reticulum stress (ERS) and reduce the level of autophagy factors through regulating the PERK-eIF2α-ATF4 pathway, thereby inhibiting the proliferation of the intima of blood vessels damaged by balloon injury (BI) and preventing the occurrence of ISR. In this study, a 2F Fogarty balloon was used to establish a common carotid artery (CCA) BI model in male Sprague-Dawley rats. Then, HTJDTLD (16.33 g/kg/d) or atorvastatin (1.19 mg/kg/d) was administered by gavage. Four weeks later, hematoxylin-eosin (HE) and Masson staining of the injured CCA were performed to observe the histological changes in the CCA. Immunohistochemistry (IHC) was used to assess the proliferation and dedifferentiation of vascular smooth muscle cells (VSMCs) in the CCA. Western blotting and RT-PCR were used to measure the expression of ERS- and autophagy-related proteins and mRNAs in the CCA. The results indicated that HTJDTLD significantly alleviated BI-induced carotid artery intimal hyperplasia and fibrosis and reduced the neointimal area (NIA) and NIA/medial area (MA) ratio. In addition, HTJDTLD inhibited the proliferation and dedifferentiation of VSMCs, reduced the expression of proliferating cell nuclear antigen (PCNA), and increased the smooth-muscle-α-actin- (SMα-actin-) positive area. HTJDTLD also significantly reduced the expression of the ERS-related factors: GRP78, p-PERK/PERK, p-eIF2α/eIF2α, ATF4, and CHOP. In addition, the expression of the autophagy-related factors, Beclin1, LC3B, and ATG12, was significantly decreased. In addition, in vitro experiments showed that HTJDTLD inhibited the above-mentioned ERS signal molecules in human umbilical vein endothelial cells (HUVEC) and rat aortic smooth muscle cells (A7R5) induced by tunicamycin (TM) and played a crucial role in protecting cells from damage. HTJDTLD may be a very promising drug for the treatment of ISR.
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Dent P, Booth L, Roberts JL, Poklepovic A, Cridebring D, Reiman EM. Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43. Aging (Albany NY) 2021; 13:17097-17117. [PMID: 34252884 PMCID: PMC8312464 DOI: 10.18632/aging.203297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/02/2021] [Indexed: 12/13/2022]
Abstract
Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.
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Affiliation(s)
- Paul Dent
- Department of Biochemistry and Molecular Biology, Richmond, VA 23298, USA
| | - Laurence Booth
- Department of Biochemistry and Molecular Biology, Richmond, VA 23298, USA
| | - Jane L Roberts
- Department of Pharmacology and Toxicology, Richmond, VA 23298, USA
| | - Andrew Poklepovic
- Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Derek Cridebring
- Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, USA
| | - Eric M Reiman
- Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, USA.,Banner Alzheimer's Institute, Phoenix, AZ 85006, USA
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Pavlović N, Heindryckx F. Exploring the Role of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma through mining of the Human Protein Atlas. BIOLOGY 2021; 10:biology10070640. [PMID: 34356495 PMCID: PMC8301178 DOI: 10.3390/biology10070640] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/30/2021] [Accepted: 07/07/2021] [Indexed: 12/22/2022]
Abstract
Simple Summary Hepatocellular carcinoma is a highly deadly primary liver cancer. It is usually diagnosed at a late stage, when therapeutic options are scarce, and the lack of predictive biomarkers poses a challenge for early detection. A known hallmark of hepatocellular carcinoma is the accumulation of misfolded proteins in the endoplasmic reticulum (ER), known as ER-stress. Growing experimental evidence suggests that ER-stress is involved in liver cancer initiation and progression. However, it remains unclear if ER-stress markers can be used as therapeutic targets or biomarkers for patients with liver cancer. In this study, we evaluated the prognostic value of proteins involved in managing ER-stress in liver cancer by mining a publicly available patient-derived database, the Human Protein Atlas. We thereby identified 44 ER-stress-associated proteins as prognostic markers in liver cancer. Furthermore, we discussed the expression of these markers in relation to disease stage, age, sex, ethnicity, and tissue localization. Abstract Endoplasmic reticulum (ER) stress and actors of unfolded protein response (UPR) have emerged as key hallmarks of hepatocarcinogenesis. Numerous reports have shown that the main actors in the UPR pathways are upregulated in HCC and contribute to the different facets of tumor initiation and disease progression. Furthermore, ER-stress inducers and inhibitors have shown success in preclinical HCC models. Despite the mounting evidence of the UPR’s involvement in HCC pathogenesis, it remains unclear how ER-stress components can be used safely and effectively as therapeutic targets or predictive biomarkers for HCC patients. In an effort to add a clinical context to these findings and explore the translational potential of ER-stress in HCC, we performed a systematic overview of UPR-associated proteins as predictive biomarkers in HCC by mining the Human Protein Atlas database. Aside from evaluating the prognostic value of these markers in HCC, we discussed their expression in relation to patient age, sex, ethnicity, disease stage, and tissue localization. We thereby identified 44 UPR-associated proteins as unfavorable prognostic markers in HCC. The expression of these markers was found to be higher in tumors compared to the stroma of the hepatic HCC patient tissues.
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PERK/ATF4-Dependent ZFAS1 Upregulation Is Associated with Sorafenib Resistance in Hepatocellular Carcinoma Cells. Int J Mol Sci 2021; 22:ijms22115848. [PMID: 34072570 PMCID: PMC8199104 DOI: 10.3390/ijms22115848] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/27/2021] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced hepatocellular carcinoma (HCC) patients. However, this drug only provides a short improvement of patients' overall survival, and drug resistance is commonly developed. Thus, the identification of resistant factor(s) or biomarker(s) is needed to develop more efficient therapeutic strategies. Long, non-coding RNAs (lncRNAs) have recently been viewed as attractive cancer biomarkers and drive many important cancer phenotypes. A lncRNA, ZFAS1 (ZNFX1 antisense RNA 1) has been found to promote HCC metastasis. This study found that sorafenib induced ZFAS1 expression specifically in sorafenib-resistant HCC cells. Although ZFAS1 knockdown did not restore the sensitivity of HCC cells to sorafenib, its expression may act as a resistant biomarker for sorafenib therapy. Bioinformatics analysis predicted that sorafenib tended to induce pathways related to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in sorafenib-resistant HCC cells. In vitro experimental evidence suggested that sorafenib induced protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-dependent ZFAS1 expression, and sorafenib resistance could be overcome by PERK/ATF inhibitors. Therefore, PERK/ATF4/ZFAS1 signaling axis might be an attractive therapeutic and prognostic biomarker for sorafenib therapy in HCC.
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Melatonin Downregulates PD-L1 Expression and Modulates Tumor Immunity in KRAS-Mutant Non-Small Cell Lung Cancer. Int J Mol Sci 2021; 22:ijms22115649. [PMID: 34073318 PMCID: PMC8199131 DOI: 10.3390/ijms22115649] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 12/18/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) patients harboring a KRAS mutation have unfavorable therapeutic outcomes with chemotherapies, and the mutation also renders tolerance to immunotherapies. There is an unmet need for a new strategy for overcoming immunosuppression in KRAS-mutant NSCLC. The recently discovered role of melatonin demonstrates a wide spectrum of anticancer impacts; however, the effect of melatonin on modulating tumor immunity is largely unknown. In the present study, melatonin treatment significantly reduced cell viability accompanied by inducing cell apoptosis in KRAS-mutant NSCLC cell lines including A549, H460, and LLC1 cells. Mechanistically, we found that lung cancer cells harboring the KRAS mutation exhibited a higher level of programmed death ligand 1 (PD-L1). However, treatment with melatonin substantially downregulated PD-L1 expressions in both the presence and absence of interferon (IFN)-γ stimulation. Moreover, KRAS-mutant lung cancer cells exhibited higher Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) levels, and PD-L1 expression was positively correlated with YAP and TAZ in lung cancer cells. Treatment with melatonin effectively suppressed YAP and TAZ, which was accompanied by downregulation of YAP/TAZ downstream gene expressions. The combination of melatonin and an inhibitor of YAP/TAZ robustly decreased YAP and PD-L1 expressions. Clinical analysis using public databases revealed that PD-L1 expression was positively correlated with YAP and TAZ in patients with lung cancer, and PD-L1 overexpression suggested poor survival probability. An animal study further revealed that administration of melatonin significantly inhibited tumor growth and modulated tumor immunity in a syngeneic mouse model. Together, our data revealed a novel antitumor mechanism of melatonin in modulating the immunosuppressive tumor microenvironment by suppressing the YAP/PD-L1 axis and suggest the therapeutic potential of melatonin for treating NSCLC.
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Cao S, Tang J, Huang Y, Li G, Li Z, Cai W, Yuan Y, Liu J, Huang X, Zhang H. The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance. Front Mol Biosci 2021; 8:620514. [PMID: 33928116 PMCID: PMC8076597 DOI: 10.3389/fmolb.2021.620514] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/12/2021] [Indexed: 12/24/2022] Open
Abstract
Endoplasmic reticulum stress (ERS), which refers to a series of adaptive responses to the disruption of endoplasmic reticulum (ER) homeostasis, occurs when cells are treated by drugs or undergo microenvironmental changes that cause the accumulation of unfolded/misfolded proteins. ERS is one of the key responses during the drug treatment of solid tumors. Drugs induce ERS by reactive oxygen species (ROS) accumulation and Ca2+ overload. The unfolded protein response (UPR) is one of ERS. Studies have indicated that the mechanism of ERS-mediated drug resistance is primarily associated with UPR, which has three main sensors (PERK, IRE1α, and ATF6). ERS-mediated drug resistance in solid tumor cells is both intrinsic and extrinsic. Intrinsic ERS in the solid tumor cells, the signal pathway of UPR-mediated drug resistance, includes apoptosis inhibition signal pathway, protective autophagy signal pathway, ABC transporter signal pathway, Wnt/β-Catenin signal pathway, and noncoding RNA. Among them, apoptosis inhibition is one of the major causes of drug resistance. Drugs activate ERS and its downstream antiapoptotic proteins, which leads to drug resistance. Protective autophagy promotes the survival of solid tumor cells by devouring the damaged organelles and other materials and providing new energy for the cells. ERS induces protective autophagy by promoting the expression of autophagy-related genes, such as Beclin-1 and ATG5–ATG12. ABC transporters pump drugs out of the cell, which reduces the drug-induced apoptosis effect and leads to drug resistance. In addition, the Wnt/β-catenin signal pathway is also involved in the drug resistance of solid tumor cells. Furthermore, noncoding RNA regulates the ERS-mediated survival and death of solid tumor cells. Extrinsic ERS in the solid tumor cells, such as ERS in immune cells of the tumor microenvironment (TME), also plays a crucial role in drug resistance by triggering immunosuppression. In immune system cells, ERS in dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) influences the antitumor function of normal T cells, which results in immunosuppression. Meanwhile, ERS in T cells can also cause impaired functioning and apoptosis, leading to immunosuppression. In this review, we highlight the core molecular mechanism of drug-induced ERS involved in drug resistance, thereby providing a new strategy for solid tumor treatment.
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Affiliation(s)
- Shulong Cao
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Jingyi Tang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Yichun Huang
- Clinical Medical College, Hubei University of Science and Technology, Xianning, China
| | - Gaofeng Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Zhuoya Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Wenqi Cai
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Yuning Yuan
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Junlong Liu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Xuqun Huang
- Edong Healthcare Group, Department of Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China
| | - Haiyuan Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
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Mehrzadi S, Pourhanifeh MH, Mirzaei A, Moradian F, Hosseinzadeh A. An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell Int 2021; 21:188. [PMID: 33789681 PMCID: PMC8011077 DOI: 10.1186/s12935-021-01892-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/23/2021] [Indexed: 12/19/2022] Open
Abstract
Cancers are serious life-threatening diseases which annually are responsible for millions of deaths across the world. Despite many developments in therapeutic approaches for affected individuals, the rate of morbidity and mortality is high. The survival rate and life quality of cancer patients is still low. In addition, the poor prognosis of patients and side effects of the present treatments underscores that finding novel and effective complementary and alternative therapies is a critical issue. Melatonin is a powerful anticancer agent and its efficiency has been widely documented up to now. Melatonin applies its anticancer abilities through affecting various mechanisms including angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Regarding the implication of mentioned cellular processes in cancer pathogenesis, we aimed to further evaluate the anticancer effects of melatonin via these mechanisms.
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Affiliation(s)
- Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Mirzaei
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Farid Moradian
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Zou Y, Sun H, Guo Y, Shi Y, Jiang Z, Huang J, Li L, Jiang F, Lin Z, Wu J, Zhou R, Liu Y, Ao L. Integrative Pan-Cancer Analysis Reveals Decreased Melatonergic Gene Expression in Carcinogenesis and RORA as a Prognostic Marker for Hepatocellular Carcinoma. Front Oncol 2021; 11:643983. [PMID: 33842355 PMCID: PMC8029983 DOI: 10.3389/fonc.2021.643983] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/02/2021] [Indexed: 12/13/2022] Open
Abstract
Background Melatonin has been shown to play a protective role in the development and progression of cancer. However, the relationship between alterations in the melatonergic microenvironment and cancer development has remained unclear. Methods We performed a comprehensive investigation on 12 melatonergic genes and their relevance to cancer occurrence, progression and survival by integrating multi-omics data from microarray analysis and RNA sequencing across 11 cancer types. Specifically, the 12 melatonergic genes that we investigated, which reflect the melatonergic microenvironment, included three membrane receptor genes, three nuclear receptor genes, two intracellular receptor genes, one synthetic gene, and three metabolic genes. Results Widely coherent underexpression of nuclear receptor genes, intracellular receptor genes, and metabolic genes was observed in cancerous samples from multiple cancer types compared to that in normal samples. Furthermore, genomic and/or epigenetic alterations partially contributed to these abnormal expression patterns in cancerous samples. Moreover, the majority of melatonergic genes had significant prognostic effects in predicting overall survival. Nevertheless, few corresponding alterations in expression were observed during cancer progression, and alterations in expression patterns varied greatly across cancer types. However, the association of melatonergic genes with one specific cancer type, hepatocellular carcinoma, identified RORA as a tumor suppressor and a prognostic marker for patients with hepatocellular carcinoma. Conclusions Overall, our study revealed decreased melatonergic gene expression in various cancers, which may help to better elucidate the relationship between melatonin and cancer development. Taken together, our findings highlight the potential prognostic significance of melatonergic genes in various cancers.
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Affiliation(s)
- Yi Zou
- Department of Automation and Key Laboratory of China MOE for System Control and Information Processing, Shanghai Jiao Tong University, Shanghai, China.,Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Huaqin Sun
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yating Guo
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yidan Shi
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zhiyu Jiang
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Jingxuan Huang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Li Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Department of Cell Biology and Genetics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Fengle Jiang
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zeman Lin
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Junling Wu
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Ruixiang Zhou
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yuncai Liu
- Department of Automation and Key Laboratory of China MOE for System Control and Information Processing, Shanghai Jiao Tong University, Shanghai, China
| | - Lu Ao
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
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Autophagy, an accomplice or antagonist of drug resistance in HCC? Cell Death Dis 2021; 12:266. [PMID: 33712559 PMCID: PMC7954824 DOI: 10.1038/s41419-021-03553-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 02/13/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal malignancy characterized by poor prognosis and a low 5-year survival rate. Drug treatment is proving to be effective in anti-HCC. However, only a small number of HCC patients exhibit sensitive responses, and drug resistance occurs frequently in advanced patients. Autophagy, an evolutionary process responsible for the degradation of cellular substances, is closely associated with the acquisition and maintenance of drug resistance for HCC. This review focuses on autophagic proteins and explores the intricate relationship between autophagy and cancer stem cells, tumor-derived exosomes, and noncoding RNA. Clinical trials involved in autophagy inhibition combined with anticancer drugs are also concerned.
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