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Wang G, Jin W, Zhang L, Dong M, Zhang X, Zhou Z, Wang X. SLC50A1 inhibits the doxorubicin sensitivity in hepatocellular carcinoma cells through regulating the tumor glycolysis. Cell Death Discov 2024; 10:495. [PMID: 39695152 DOI: 10.1038/s41420-024-02261-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/20/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
Metabolic reprogramming has been found to be closely associated with the occurrence and development of hepatocellular carcinoma (HCC). The relationship between SLC50A1, a member of the SLC family involved in glucose transmembrane transport, and HCC remains unclear. This study aims to investigate the function and underlying mechanisms of SLC50A1 in the occurrence and progression of HCC. Based on bioinformatics analysis and clinical sample testing, we observed a significant upregulation of SLC50A1 in HCC, which is correlated with unfavorable prognosis in HCC patients. Additionally, there is a noticeable correlation between the expressions of SLC50A1 and METTL3. Further in vitro and in vivo experiments confirmed that SLC50A1 can regulate cellular glycolysis and the cell cycle, thereby promoting the proliferation of HCC cells while reducing apoptosis. Moreover, our findings indicate that SLC50A1 enhances resistance of HCC cells to DOX and 2-DG. Furthermore, we discovered that the m6A methyltransferase METTL3 mediates the methylation modification of SLC50A1. The recognition and binding of the modified SLC50A1 by IGF2BP2 subsequently promote its stability and translational expression. Consequently, our research identifies the METTL3/SLC50A1 axis as a novel therapeutic target in the context of HCC.
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Affiliation(s)
- Ganggang Wang
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Wenzhi Jin
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Lianmei Zhang
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Meiyuan Dong
- Graduate School of Hebei Medical University, Shijiazhuang, People's Republic of China
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Xin Zhang
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Zhijie Zhou
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Xiaoliang Wang
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
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2
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Hu T, Liu CH, Lei M, Zeng Q, Li L, Tang H, Zhang N. Metabolic regulation of the immune system in health and diseases: mechanisms and interventions. Signal Transduct Target Ther 2024; 9:268. [PMID: 39379377 PMCID: PMC11461632 DOI: 10.1038/s41392-024-01954-6] [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: 03/27/2024] [Revised: 07/18/2024] [Accepted: 08/11/2024] [Indexed: 10/10/2024] Open
Abstract
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.
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Affiliation(s)
- Tengyue Hu
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Min Lei
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Qingmin Zeng
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Division of Renal and endocrinology, Qin Huang Hospital, Xi'an, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Nannan Zhang
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China.
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
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3
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Zhou S, Xu H, Duan Y, Tang Q, Huang H, Bi F. Survival mechanisms of circulating tumor cells and their implications for cancer treatment. Cancer Metastasis Rev 2024; 43:941-957. [PMID: 38436892 DOI: 10.1007/s10555-024-10178-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/26/2024] [Indexed: 03/05/2024]
Abstract
Metastasis remains the principal trigger for relapse and mortality across diverse cancer types. Circulating tumor cells (CTCs), which originate from the primary tumor or its metastatic sites, traverse the vascular system, serving as precursors in cancer recurrence and metastasis. Nevertheless, before CTCs can establish themselves in the distant parenchyma, they must overcome significant challenges present within the circulatory system, including hydrodynamic shear stress (HSS), oxidative damage, anoikis, and immune surveillance. Recently, there has been a growing body of compelling evidence suggesting that a specific subset of CTCs can persist within the bloodstream, but the precise mechanisms of their survival remain largely elusive. This review aims to present an outline of the survival challenges encountered by CTCs and to summarize the recent advancements in understanding the underlying survival mechanisms, suggesting their implications for cancer treatment.
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Affiliation(s)
- Shuang Zhou
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Huanji Xu
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yichun Duan
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Qiulin Tang
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Huixi Huang
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Feng Bi
- Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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4
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Yan Y, Li S, Su L, Tang X, Chen X, Gu X, Yang G, Chi H, Huang S. Mitochondrial inhibitors: a new horizon in breast cancer therapy. Front Pharmacol 2024; 15:1421905. [PMID: 39027328 PMCID: PMC11254633 DOI: 10.3389/fphar.2024.1421905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 06/10/2024] [Indexed: 07/20/2024] Open
Abstract
Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.
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Affiliation(s)
- Yalan Yan
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Sijie Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lanqian Su
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xinrui Tang
- Paediatrics Department, Southwest Medical University, Luzhou, China
| | - Xiaoyan Chen
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiang Gu
- Biology Department, Southern Methodist University, Dallas, TX, United States
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH, United States
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Shangke Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Peng C, Yang P, Zhang D, Jin C, Peng W, Wang T, Sun Q, Chen Z, Feng Y, Sun Y. KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2. Acta Pharm Sin B 2024; 14:2959-2976. [PMID: 39027256 PMCID: PMC11252482 DOI: 10.1016/j.apsb.2024.04.024] [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: 01/13/2024] [Revised: 03/01/2024] [Accepted: 04/15/2024] [Indexed: 07/20/2024] Open
Abstract
Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.
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Affiliation(s)
- Chaofan Peng
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Peng Yang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Dongsheng Zhang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Chi Jin
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Wen Peng
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Tuo Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Qingyang Sun
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Zhihao Chen
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
| | - Yifei Feng
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing 210029, China
| | - Yueming Sun
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- Colorectal Institute of Nanjing Medical University, Nanjing 210029, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing 210029, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing 210029, China
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Li Y, Xie Z, Lei X, Yang X, Huang S, Yuan W, Deng X, Wang Z, Tang G. Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities. Bioorg Chem 2024; 144:107160. [PMID: 38301426 DOI: 10.1016/j.bioorg.2024.107160] [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: 01/08/2024] [Revised: 01/23/2024] [Accepted: 01/27/2024] [Indexed: 02/03/2024]
Abstract
Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.
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Affiliation(s)
- Yiyang Li
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhizhong Xie
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiaoyan Yang
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Sheng Huang
- Jiuzhitang Co., Ltd, Changsha, Hunan 410007, China
| | - Weixi Yuan
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiangping Deng
- The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
| | - Zhe Wang
- The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
| | - Guotao Tang
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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Zhang Y, Ji X, Wang Y. ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis. Gland Surg 2024; 13:209-224. [PMID: 38455357 PMCID: PMC10915417 DOI: 10.21037/gs-24-44] [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: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 03/09/2024]
Abstract
Background Anoikis presents a significant barrier in the metastasis of cancer. As the most aggressive type of thyroid cancer, anaplastic thyroid cancer (ATC) exhibits a high risk of metastasis and is characterized by high mortality. Therefore, investigating the molecular mechanisms of anoikis resistance in ATC is important for devising therapeutic targets in clinical research. Methods Differentially Expressed Genes were screened in ATC cells under attached and detached culture conditions with RNA-seq. Investigate the impact of enolase 2 (ENO2) on apoptosis and spheroid formation by gain and loss of function. Changes of reactive oxygen species (ROS), glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) were detected to assess redox balance. The transcriptional regulatory role of signal transducer and activator of transcription 1 (STAT1) on ENO2 was validated through Dual-Luciferase Reporter Gene Assay. Explore the impact of ENO2 expression on the formation of lung metastases in nude mice. Results We found that the glycolysis process was activated in detached ATC cells. Several genes in the glycolysis process, particularly ENO2, a member of the enolase superfamily was upregulated in ATC cells cultured in suspension. The upregulation of ENO2 enabled the maintenance of redox balance by supplying GSH and NADPH, thereby preventing cells from undergoing anoikis. In terms of mechanism, the expression of STAT1 was enhanced in anoikis resistance cells, which in turn positively regulated the expression of ENO2. In vivo, ENO2-suppressed ATC cells resulted in a significantly lower rate of lung colonization compared to control ATC cells. Conclusions Stable expression of ENO2 and the maintenance of redox balance played a pivotal role in facilitating anoikis resistance of ATC.
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Affiliation(s)
- Yu Zhang
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoyu Ji
- Department of Oncology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yu Wang
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Jiang Z, He J, Zhang B, Wang L, Long C, Zhao B, Yang Y, Du L, Luo W, Hu J, Hong X. A Potential "Anti-Warburg Effect" in Circulating Tumor Cell-mediated Metastatic Progression? Aging Dis 2024; 16:AD.2023.1227. [PMID: 38300633 PMCID: PMC11745448 DOI: 10.14336/ad.2023.1227] [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: 09/16/2023] [Accepted: 12/27/2023] [Indexed: 02/02/2024] Open
Abstract
Metabolic reprogramming is a defining hallmark of cancer metastasis, warranting thorough exploration. The tumor-promoting function of the "Warburg Effect", marked by escalated glycolysis and restrained mitochondrial activity, is widely acknowledged. Yet, the functional significance of mitochondria-mediated oxidative phosphorylation (OXPHOS) during metastasis remains controversial. Circulating tumor cells (CTCs) are considered metastatic precursors that detach from primary or secondary sites and harbor the potential to seed distant metastases through hematogenous dissemination. A comprehensive metabolic characterization of CTCs faces formidable obstacles, including the isolation of these rare cells from billions of blood cells, coupled with the complexities of ex vivo-culturing of CTC lines or the establishment of CTC-derived xenograft models (CDX). This review summarized the role of the "Warburg Effect" in both tumorigenesis and CTC-mediated metastasis. Intriguingly, bioinformatic analysis of single-CTC transcriptomic studies unveils a potential OXPHOS dominance over Glycolysis signature genes across several important cancer types. From these observations, we postulate a potential "Anti-Warburg Effect" (AWE) in CTCs-a metabolic shift bridging primary tumors and metastases. The observed AWE could be clinically important as they are significantly correlated with therapeutic response in melanoma and prostate patients. Thus, unraveling dynamic metabolic regulations within CTC populations might reveal an additional layer of regulatory complexities of cancer metastasis, providing an avenue for innovative anti-metastasis therapies.
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Affiliation(s)
- Zhuofeng Jiang
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Jiapeng He
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Binyu Zhang
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Liping Wang
- Department of Oncology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong, China.
| | - Chunhao Long
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Boxi Zhao
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Yufan Yang
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Longxiang Du
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Weiren Luo
- Cancer Research Institute, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Diseases, Shenzhen, China.
| | - Jianyang Hu
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
- Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Xin Hong
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
- Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, Guangdong, China.
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, Guangdong, China.
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Banerjee D, Boboila S, Okochi S, Angelastro JM, Kadenhe-Chiweshe AV, Lopez G, Califano A, Connolly EP, Greene LA, Yamashiro DJ. Activating Transcription Factor 5 Promotes Neuroblastoma Metastasis by Inducing Anoikis Resistance. CANCER RESEARCH COMMUNICATIONS 2023; 3:2518-2530. [PMID: 38014922 PMCID: PMC10714915 DOI: 10.1158/2767-9764.crc-23-0154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/20/2023] [Accepted: 11/16/2023] [Indexed: 11/29/2023]
Abstract
MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion-induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. SIGNIFICANCE This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma.
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Affiliation(s)
- Debarshi Banerjee
- Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
| | - Shuobo Boboila
- Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
- Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York
| | - Shunpei Okochi
- Department of Surgery, Columbia University Irving Medical Center, New York, New York
| | - James M. Angelastro
- Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, California
| | | | - Gonzalo Lopez
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York
| | - Andrea Califano
- Department of Systems Biology, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Eileen P. Connolly
- Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
| | - Lloyd A. Greene
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Darrell J. Yamashiro
- Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
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10
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Fnu G, Weber GF. Osteopontin induces mitochondrial biogenesis in deadherent cancer cells. Oncotarget 2023; 14:957-969. [PMID: 38039408 PMCID: PMC10691814 DOI: 10.18632/oncotarget.28540] [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: 08/10/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023] Open
Abstract
Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms. Here, we report that autocrine Osteopontin does indeed stimulate an increase in mitochondrial size, with the splice variant -c being more effective than the full-length form -a. Osteopontin-c achieves this via its receptor CD44v, jointly with the upregulation and co-ligation of the chloride-dependent cystine-glutamate transporter SLC7A11. The signaling proceeds through activation of the known mitochondrial biogenesis inducer PGC-1 (which acts as a transcription coactivator). Peroxide is an important intermediate in this cascade, but surprisingly acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation. In vivo, suppression of the biogenesis-inducing mechanisms leads to a reduction in disseminated tumor mass. This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis - both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.
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Affiliation(s)
- Gulimirerouzi Fnu
- University of Cincinnati Academic Health Center, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA
| | - Georg F. Weber
- University of Cincinnati Academic Health Center, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA
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11
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Sobhi Amjad Z, Shojaeian A, Sadri Nahand J, Bayat M, Taghizadieh M, Rostamian M, Babaei F, Moghoofei M. Oncoviruses: Induction of cancer development and metastasis by increasing anoikis resistance. Heliyon 2023; 9:e22598. [PMID: 38144298 PMCID: PMC10746446 DOI: 10.1016/j.heliyon.2023.e22598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 11/07/2023] [Accepted: 11/15/2023] [Indexed: 12/26/2023] Open
Abstract
The phenomenon of cell death is a vital aspect in the regulation of aberrant cells such as cancer cells. Anoikis is a kind of cell death that occurs when cells get separated from the extracellular matrix. Some cancer cells can inhibit anoikis in order to progress metastasis. One of the key variables that might be implicated in anoikis resistance (AR) is viral infections. The most important viruses involved in this process are Epstein-Barr virus, human papillomavirus, hepatitis B virus, human herpes virus 8, human T-cell lymphotropic virus type 1, and hepatitis C virus. A better understanding of how carcinogenic viruses suppress anoikis might be helpful in developing an effective treatment for virus-associated cancers. In the current study, we review the role of the mentioned viruses and their gene products in anoikis inhibition.
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Affiliation(s)
- Zahra Sobhi Amjad
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Shojaeian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mosayeb Rostamian
- Nosocomial Infections Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farhad Babaei
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohsen Moghoofei
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Infectious Diseases Research Center, Health Research Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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12
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Cunha A, Silva PMA, Sarmento B, Queirós O. Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance. Pharmaceutics 2023; 15:2610. [PMID: 38004589 PMCID: PMC10675572 DOI: 10.3390/pharmaceutics15112610] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/27/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
The "Warburg effect" consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation.
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Affiliation(s)
- Andrea Cunha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 4585-116 Gandra, Portugal; (A.C.); (P.M.A.S.); (B.S.)
| | - Patrícia M. A. Silva
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 4585-116 Gandra, Portugal; (A.C.); (P.M.A.S.); (B.S.)
- 1H—TOXRUN—One Health Toxicology Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 3810-193 Gandra, Portugal
| | - Bruno Sarmento
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 4585-116 Gandra, Portugal; (A.C.); (P.M.A.S.); (B.S.)
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences—CESPU (IUCS—CESPU), 4585-116 Gandra, Portugal; (A.C.); (P.M.A.S.); (B.S.)
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13
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Pang M, Sun X, He T, Liang H, Yang H, Chen J. Development of a prognostic model based on anoikis-related genes for predicting clinical prognosis and immunotherapy of hepatocellular carcinoma. Aging (Albany NY) 2023; 15:10253-10271. [PMID: 37787988 PMCID: PMC10599733 DOI: 10.18632/aging.205073] [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: 04/21/2023] [Accepted: 06/19/2023] [Indexed: 10/04/2023]
Abstract
Hepatocellular Carcinoma (HCC) is the predominant cause of cancer-related mortality worldwide. The majority of HCC patients are diagnosed at advanced stages of the disease, with a high likelihood of metastasis and unfavorable prognosis. Anoikis resistance is a crucial factor contributing to tumor invasion and metastasis, although its specific role in HCC remains unclear. Based on the results of univariate Cox regression and least absolute shrink-age and selection operator (LASSO) analysis, a subset of anoikis-related genes (ARGs) significantly associated with overall survival (OS) was identified. A multivariate Cox regression analysis subsequently identified PDK4, STK11, and TFDP1 as three prognostic ARGs, which were then used to establish a prognostic risk model. Differences in OS caused by risk stratification in HCC patients were demonstrated. The nomogram analysis indicated that the ARGs prognostic signature served as an independent prognostic predictor. In vitro experiments further confirmed the abnormal expression of selected ARGs in HCC. The association between risk scores and OS was further examined through Kaplan-Meier analysis, CIBERSORT analysis, and single-sample gene set enrichment analysis (ssGSEA). This study is a pioneering effort to integrate multiple ARGs and establish a risk-predictive model, providing a unique perspective for the development of personalized and precise therapeutic strategies for HCC.
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Affiliation(s)
- Mu Pang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong 518000, China
| | - Xizhe Sun
- Research Center for Drug Safety Evaluation of Hainan, Hainan Medical University, Haikou, Hainan 571199, China
| | - Ting He
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong 518000, China
| | - Huichao Liang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong 518000, China
| | - Hao Yang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong 518000, China
| | - Jun Chen
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong 518000, China
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14
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He Z, Gu Y, Yang H, Fu Q, Zhao M, Xie Y, Liu Y, Du W. Identification and verification of a novel anoikis-related gene signature with prognostic significance in clear cell renal cell carcinoma. J Cancer Res Clin Oncol 2023; 149:11661-11678. [PMID: 37402968 DOI: 10.1007/s00432-023-05012-6] [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: 05/12/2023] [Accepted: 06/19/2023] [Indexed: 07/06/2023]
Abstract
PURPOSE Clear cell renal cell carcinomas (ccRCCs) are the most common form of renal cancer in the world. The loss of extracellular matrix (ECM) stimulates cell apoptosis, known as anoikis. A resistance to anoikis in cancer cells is believed to contribute to tumor malignancy, particularly metastasis; however, the potential influence of anoikis on the prognosis of ccRCC patients is not fully understood. METHODS In this study, anoikis-related genes (ARGs) with discrepant expression were selected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The anoikis-related gene signature (ARS) was built using a combination of the univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses. ARS was also evaluated for their prognostic value. We explored the tumor microenvironment and enrichment pathways between different clusters of ccRCC. We also examined differences in clinical characteristics, immune cell infiltration and drug sensitivity between the high- and low-risk sets. In addition, we utilized three external databases and quantitative real-time polymerase chain reaction (qRT-PCR) to validate the expression and prognosis of ARGs. RESULTS Eight ARGs (PLAUR, HMCN1, CDKN2A, BID, GLI2, PLG, PRKCQ and IRF6) were identified as anoikis-related prognostic factors. According to Kaplan-Meier (KM) analysis, ccRCC patients with high-risk ARGs have a worse prognosis. The risk score was found to be a significant independent prognostic indicator. According to tumor microenvironment (TME) scores, stromal score, immune score, and estimated score of the high-risk group were superior to those of the low-risk group. There were significant differences between the two groups regarding the amount of infiltrated immune cells, immune checkpoint expression as well as drug sensitivity. A nomogram was constructed using ccRCC clinical features and risk scores. The signature and the nomogram both performed well in predicting overall survival (OS) for ccRCC patients. According to a decision curve analysis (DCA), clinical treatment options for patients with ccRCC could be improved using this model. CONCLUSION The results of validation from external databases and qRT-PCR were basically agreement with findings in TCGA and GEO databases. The ARS serving as biomarkers may provide an important reference for individual therapy of ccRCC patients.
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Affiliation(s)
- Zhiqiang He
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Yufan Gu
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Huan Yang
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Qian Fu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Maofang Zhao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Yuhan Xie
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Yi Liu
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
| | - Wenlong Du
- Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
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15
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Chen H, Li X, Li F, Li Y, Chen F, Zhang L, Ye F, Gong M, Bu H. Prediction of coexisting invasive carcinoma on ductal carcinoma in situ (DCIS) lesions by mass spectrometry imaging. J Pathol 2023; 261:125-138. [PMID: 37555360 DOI: 10.1002/path.6154] [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: 10/15/2022] [Revised: 05/16/2023] [Accepted: 06/07/2023] [Indexed: 08/10/2023]
Abstract
Due to limited biopsy samples, ~20% of DCIS lesions confirmed by biopsy are upgraded to invasive ductal carcinoma (IDC) upon surgical resection. Avoiding underestimation of IDC when diagnosing DCIS has become an urgent challenge in an era discouraging overtreatment of DCIS. In this study, the metabolic profiles of 284 fresh frozen breast samples, including tumor tissues and adjacent benign tissues (ABTs) and distant surrounding tissues (DSTs), were analyzed using desorption electrospray ionization-mass spectrometry (DESI-MS) imaging. Metabolomics analysis using DESI-MS data revealed significant differences in metabolite levels, including small-molecule antioxidants, long-chain polyunsaturated fatty acids (PUFAs) and phospholipids between pure DCIS and IDC. However, the metabolic profile in DCIS with invasive carcinoma components clearly shifts to be closer to adjacent IDC components. For instance, DCIS with invasive carcinoma components showed lower levels of antioxidants and higher levels of free fatty acids compared to pure DCIS. Furthermore, the accumulation of long-chain PUFAs and the phosphatidylinositols (PIs) containing PUFA residues may also be associated with the progression of DCIS. These distinctive metabolic characteristics may offer valuable indications for investigating the malignant potential of DCIS. By combining DESI-MS data with machine learning (ML) methods, various breast lesions were discriminated. Importantly, the pure DCIS components were successfully distinguished from the DCIS components in samples with invasion in postoperative specimens by a Lasso prediction model, achieving an AUC value of 0.851. In addition, pixel-level prediction based on DESI-MS data enabled automatic visualization of tissue properties across whole tissue sections. Summarily, DESI-MS imaging on histopathological sections can provide abundant metabolic information about breast lesions. By analyzing the spatial metabolic characteristics in tissue sections, this technology has the potential to facilitate accurate diagnosis and individualized treatment of DCIS by inferring the presence of IDC components surrounding DCIS lesions. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Hong Chen
- Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, PR China
- Key Laboratory of Transplant Engineering and Immunology of the National Health Commission, West China Hospital, Sichuan University, Chengdu, PR China
| | - Xin Li
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Fengling Li
- Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, PR China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yijie Li
- Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, PR China
- Key Laboratory of Transplant Engineering and Immunology of the National Health Commission, West China Hospital, Sichuan University, Chengdu, PR China
| | - Fei Chen
- Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, PR China
| | - Lu Zhang
- Image Processing and Parallel Computing Laboratory, School of Computer Science, Southwest Petroleum University, Chengdu, PR China
| | - Feng Ye
- Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, PR China
- Key Laboratory of Transplant Engineering and Immunology of the National Health Commission, West China Hospital, Sichuan University, Chengdu, PR China
| | - Meng Gong
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Hong Bu
- Department of Pathology and Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, PR China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, PR China
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16
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Klement RJ, Sweeney RA. Metabolic factors associated with the prognosis of oligometastatic patients treated with stereotactic body radiotherapy. Cancer Metastasis Rev 2023; 42:927-940. [PMID: 37261610 DOI: 10.1007/s10555-023-10110-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
Over the past two decades, it has been established that cancer patients with oligometastases, i.e., only a few detectable metastases confined to one or a few organs, may benefit from an aggressive local treatment approach such as the application of high-precision stereotactic body radiotherapy (SBRT). Specifically, some studies have indicated that achieving long-term local tumor control of oligometastases is associated with prolonged overall survival. This motivates investigations into which factors may modify the dose-response relationship of SBRT by making metastases more or less radioresistant. One such factor relates to the uptake of the positron emission tomography tracer 2-deoxy-2-[18F]fluoro-D-glucose (FDG) which reflects the extent of tumor cell glycolysis or the Warburg effect, respectively. Here we review the biological mechanisms how the Warburg effect drives tumor cell radioresistance and metastasis and draw connections to clinical studies reporting associations between high FDG uptake and worse clinical outcomes after SBRT for oligometastases. We further review the evidence for distinct metabolic phenotypes of metastases preferentially seeding to specific organs and their possible translation into distinct radioresistance. Finally, evidence that obesity and hyperglycemia also affect outcomes after SBRT will be presented. While delivered dose is the main determinant of a high local tumor control probability, there might be clinical scenarios when metabolic targeting could make the difference between achieving local control or not, for example when doses have to be compromised in order to spare neighboring high-risk organs, or when tumors are expected to be highly therapy-resistant due to heavy pretreatment such as chemotherapy and/or radiotherapy.
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Affiliation(s)
- Rainer J Klement
- Department of Radiotherapy and Radiation Oncology, Leopoldina Hospital Schweinfurt, Robert-Koch-Straße 10, 97422, Schweinfurt, Germany.
| | - Reinhart A Sweeney
- Department of Radiotherapy and Radiation Oncology, Leopoldina Hospital Schweinfurt, Robert-Koch-Straße 10, 97422, Schweinfurt, Germany
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17
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Su WY, Tian LY, Guo LP, Huang LQ, Gao WY. PI3K signaling-regulated metabolic reprogramming: From mechanism to application. Biochim Biophys Acta Rev Cancer 2023; 1878:188952. [PMID: 37499988 DOI: 10.1016/j.bbcan.2023.188952] [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: 06/01/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/29/2023]
Abstract
Oncogenic signaling involved in tumor metabolic reprogramming. Tumorigenesis was not only determined by the mutations or deletion of oncogenes but also accompanied by the reprogramming of cellular metabolism. Metabolic alterations play a crucial regulatory role in the development and progression of tumors. Oncogenic PI3K/AKT signaling mediates the metabolic switch in cancer cells and immune cells in the tumor microenvironment. PI3K/AKT and its downstream effector branch off and connect to multiple steps of metabolism, such as glucose, lipids, and amino acids. Thus, PI3K inhibitor could effectively regulate metabolic pathway and impede the oncogenic process and some key metabolic proteins or critical enzymes also constitute biomarkers for tumor diagnosis and treatment. In the current review, we summarize the significant effect of PI3K/AKT signaling toward tumor metabolism, it enables us to obtain the better understanding for this interaction and develop more effective therapeutic strategies targeting cancer cell metabolism.
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Affiliation(s)
- Wen Ya Su
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Lu Yao Tian
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Lan Pin Guo
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Lu Qi Huang
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Wen Yuan Gao
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
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18
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Jiao Z, Pan Y, Chen F. The Metabolic Landscape of Breast Cancer and Its Therapeutic Implications. Mol Diagn Ther 2023; 27:349-369. [PMID: 36991275 DOI: 10.1007/s40291-023-00645-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2023] [Indexed: 03/31/2023]
Abstract
Breast cancer is the most common malignant tumor globally as of 2020 and remains the second leading cause of cancer-related death among female individuals worldwide. Metabolic reprogramming is well recognized as a hallmark of malignancy owing to the rewiring of multiple biological processes, notably, glycolysis, oxidative phosphorylation, pentose phosphate pathway, as well as lipid metabolism, which support the demands for the relentless growth of tumor cells and allows distant metastasis of cancer cells. Breast cancer cells are well documented to reprogram their metabolism via mutations or inactivation of intrinsic factors such as c-Myc, TP53, hypoxia-inducible factor, and the PI3K/AKT/mTOR pathway or crosstalk with the surrounding tumor microenvironments, including hypoxia, extracellular acidification and interaction with immune cells, cancer-associated fibroblasts, and adipocytes. Furthermore, altered metabolism contributes to acquired or inherent therapeutic resistance. Therefore, there is an urgent need to understand the metabolic plasticity underlying breast cancer progression as well as to dictate metabolic reprogramming that accounts for the resistance to standard of care. This review aims to illustrate the altered metabolism in breast cancer and its underlying mechanisms, as well as metabolic interventions in breast cancer treatment, with the intention to provide strategies for developing novel therapeutic treatments for breast cancer.
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Affiliation(s)
- Zhuoya Jiao
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China
| | - Yunxia Pan
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China
| | - Fengyuan Chen
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China.
- Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China.
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19
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Poh AR, Ernst M. Functional roles of SRC signaling in pancreatic cancer: Recent insights provide novel therapeutic opportunities. Oncogene 2023:10.1038/s41388-023-02701-x. [PMID: 37120696 DOI: 10.1038/s41388-023-02701-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/19/2023] [Indexed: 05/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of <10%. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.
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Affiliation(s)
- Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC, 3084, Australia.
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC, 3084, Australia.
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20
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Nepali PR, Kyprianou N. Anoikis in phenotypic reprogramming of the prostate tumor microenvironment. Front Endocrinol (Lausanne) 2023; 14:1160267. [PMID: 37091854 PMCID: PMC10113530 DOI: 10.3389/fendo.2023.1160267] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/09/2023] [Indexed: 04/25/2023] Open
Abstract
Prostate cancer is one of the most common malignancies in males wherein 1 in 8 men are diagnosed with this disease in their lifetime. The urgency to find novel therapeutic interventions is associated with high treatment resistance and mortality rates associated with castration-resistant prostate cancer. Anoikis is an apoptotic phenomenon for normal epithelial or endothelial cells that have lost their attachment to the extracellular matrix (ECM). Tumor cells that lose their connection to the ECM can die via apoptosis or survive via anoikis resistance and thus escaping to distant organs for metastatic progression. This review discusses the recent advances made in our understanding of the signaling effectors of anoikis in prostate cancer and the approaches to translate these mechanistic insights into therapeutic benefits for reducing lethal disease outcomes (by overcoming anoikis resistance). The prostate tumor microenvironment is a highly dynamic landscape wherein the balance between androgen signaling, cell lineage changes, epithelial-mesenchymal transition (EMT), extracellular matrix interactions, actin cytoskeleton remodeling as well as metabolic changes, confer anoikis resistance and metastatic spread. Thus, these mechanisms also offer unique molecular treatment signatures, exploitation of which can prime prostate tumors to anoikis induction with a high translational significance.
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Affiliation(s)
- Prerna R. Nepali
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Natasha Kyprianou
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Department of Pathology and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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21
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Farooq Z, Ismail H, Bhat SA, Layden BT, Khan MW. Aiding Cancer's "Sweet Tooth": Role of Hexokinases in Metabolic Reprogramming. Life (Basel) 2023; 13:946. [PMID: 37109475 PMCID: PMC10141071 DOI: 10.3390/life13040946] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/24/2023] [Accepted: 03/31/2023] [Indexed: 04/08/2023] Open
Abstract
Hexokinases (HKs) convert hexose sugars to hexose-6-phosphate, thus trapping them inside cells to meet the synthetic and energetic demands. HKs participate in various standard and altered physiological processes, including cancer, primarily through the reprogramming of cellular metabolism. Four canonical HKs have been identified with different expression patterns across tissues. HKs 1-3 play a role in glucose utilization, whereas HK 4 (glucokinase, GCK) also acts as a glucose sensor. Recently, a novel fifth HK, hexokinase domain containing 1 (HKDC1), has been identified, which plays a role in whole-body glucose utilization and insulin sensitivity. Beyond the metabolic functions, HKDC1 is differentially expressed in many forms of human cancer. This review focuses on the role of HKs, particularly HKDC1, in metabolic reprogramming and cancer progression.
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Affiliation(s)
- Zeenat Farooq
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Hagar Ismail
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Sheraz Ahmad Bhat
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA
| | - Md. Wasim Khan
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
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22
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Puente-Cobacho B, Varela-López A, Quiles JL, Vera-Ramirez L. Involvement of redox signalling in tumour cell dormancy and metastasis. Cancer Metastasis Rev 2023; 42:49-85. [PMID: 36701089 PMCID: PMC10014738 DOI: 10.1007/s10555-022-10077-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 12/27/2022] [Indexed: 01/27/2023]
Abstract
Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.
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Affiliation(s)
- Beatriz Puente-Cobacho
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain
| | - Alfonso Varela-López
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - Laura Vera-Ramirez
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain. .,Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain.
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23
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Stacpoole PW, McCall CE. The pyruvate dehydrogenase complex: Life's essential, vulnerable and druggable energy homeostat. Mitochondrion 2023; 70:59-102. [PMID: 36863425 DOI: 10.1016/j.mito.2023.02.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/30/2023] [Accepted: 02/13/2023] [Indexed: 03/04/2023]
Abstract
Found in all organisms, pyruvate dehydrogenase complexes (PDC) are the keystones of prokaryotic and eukaryotic energy metabolism. In eukaryotic organisms these multi-component megacomplexes provide a crucial mechanistic link between cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. As a consequence, PDCs also influence the metabolism of branched chain amino acids, lipids and, ultimately, oxidative phosphorylation (OXPHOS). PDC activity is an essential determinant of the metabolic and bioenergetic flexibility of metazoan organisms in adapting to changes in development, nutrient availability and various stresses that challenge maintenance of homeostasis. This canonical role of the PDC has been extensively probed over the past decades by multidisciplinary investigations into its causal association with diverse physiological and pathological conditions, the latter making the PDC an increasingly viable therapeutic target. Here we review the biology of the remarkable PDC and its emerging importance in the pathobiology and treatment of diverse congenital and acquired disorders of metabolic integration.
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Affiliation(s)
- Peter W Stacpoole
- Department of Medicine (Division of Endocrinology, Metabolism and Diabetes), and Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL, United States.
| | - Charles E McCall
- Department of Internal Medicine and Translational Sciences, and Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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24
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Li J, Gao R, Zhang J. USP22 Contributes to Chemoresistance, Stemness, and EMT Phenotype of Triple-Negative Breast Cancer Cells by egulating the Warburg Effect via c-Myc Deubiquitination. Clin Breast Cancer 2023; 23:162-175. [PMID: 36528490 DOI: 10.1016/j.clbc.2022.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 11/07/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Ubiquitin-specific protease 22 (USP22) has been implicated in the progression of breast cancer, while its regulatory functions in triple-negative breast cancer (TNBC) have been rarely reported. This study aimed to elucidate the effect and mechanism of USP22 on the malignant phenotype of TNBC cells. MATERIALS AND METHODS The expression of USP22, stemness genes, and EMT-related markers were analyzed by RT-qPCR and/or Western blotting. Cell stemness was determined by cell spheroid formation, flow cytometry for CD44+/CD24-, and extreme limiting dilution analysis. Cell proliferation and cisplatin (DDP) chemoresistance of TNBC cells were assessed by CCK-8 assay and xenograft model. Glycolysis was measured by Seahorse assay. The mechanism underlying the role of USP22 was explored by Co-immunoprecipitation, ubiquitination assay, and cycloheximide-chase analysis. RESULTS USP22 expression was positively correlated with DDP resistance in TNBC patients and cells. The proliferation, spheroid number, CD44+/CD24- cells, the expression of stemness genes and EMT-related markers in TNBC cells were significantly elevated after USP22 was overexpressed; however, these parameters in DDP-resistant TNBC (TNBC/DDP) cells were significantly reduced after silencing USP22. USP22 overexpression enhanced the extracellular acidification rate, proliferation, spheroid number, CD44+/CD24- cell number, and the expression of stemness genes and EMT-related markers in TNBC/DDP cells, while these effects were restrained by glycolysis inhibitors. Mechanically, USP22 interacted with c-Myc to promote its stabilization by deubiquitination in TNBC cells. Silencing of USP22 increased DDP sensitivity and survival of mice bearing TNBC. CONCLUSION USP22 contributes to chemoresistance, stemness, and EMT phenotype of TNBC cells by suppressing the glycolysis via c-Myc deubiquitination.
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Affiliation(s)
- Jie Li
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China.
| | - Runfang Gao
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Jing Zhang
- Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan, China
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25
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Zhang Y, Shi J, Luo J, Liu C, Zhu L. Metabolic heterogeneity in early-stage lung adenocarcinoma revealed by RNA-seq and scRNA-seq. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:1844-1855. [PMID: 36692643 DOI: 10.1007/s12094-023-03082-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/09/2023] [Indexed: 01/25/2023]
Abstract
PURPOSE Cancer cells maintain cell growth, division, and survival through altered energy metabolism. However, research on metabolic reprogramming in lung adenocarcinoma (LUAD) is limited METHODS: We downloaded TCGA and GEO sequencing data. Consistent clustering with the ConsensusClusterPlus package was employed to detect the scores for four metabolism-related pathways. The LUAD samples in the TCGA dataset were clustered with ConsensusClusterPlus, and the optimal number of clusters was determined according to the cumulative distribution function (CDF). The cell score for each sample in the TCGA dataset was calculated using the MCPcounter estimate function of the MCPcounter package. RESULTS We identified two subtypes by scoring the samples based on the 4 metabolism-related pathways and cluster dimensionality reduction. The prognosis of cluster B was obviously poorer than that of cluster A in patients with LUAD. The analysis of single-nucleotide variation (SNV) data showed that the top 15 genes in the four metabolic pathways with the most mutations were TKTL2, PGK2, HK3, EHHADH, GLUD2, PKLR, TKTL1, HADHB, CPT1C, HK1, HK2, PFKL, SLC2A3, PFKFB1, and CPT1A. The IFNγ score of cluster B was significantly higher than that of cluster A. The immune T-cell lytic activity score of cluster B was significantly higher than that of cluster A. We further identified 5 immune cell subsets from single-cell sequencing data. The top 5 marker genes of B cells were IGHM, JCHAIN, IGLC3, IGHA1, and IGKC. The C0 subgroup of monocytes had a higher pentose phosphate pathway (PPP) score than the C6 subgroup. CONCLUSIONS Metabolism-related subtypes could be potential biomarkers in the prognosis prediction and treatment of LUAD.
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Affiliation(s)
- Yang Zhang
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Jiang Shi
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Junfang Luo
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Cong Liu
- Department of Geriatric Respiratory and Sleep, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lixu Zhu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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26
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Agostini M, Mancini M, Candi E. Long non-coding RNAs affecting cell metabolism in cancer. Biol Direct 2022; 17:26. [PMID: 36182907 PMCID: PMC9526990 DOI: 10.1186/s13062-022-00341-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 11/27/2021] [Indexed: 11/10/2022] Open
Abstract
Metabolic reprogramming is commonly recognized as one important hallmark of cancers. Cancer cells present significant alteration of glucose metabolism, oxidative phosphorylation, and lipid metabolism. Recent findings demonstrated that long non-coding RNAs control cancer development and progression by modulating cell metabolism. Here, we give an overview of breast cancer metabolic reprogramming and the role of long non-coding RNAs in driving cancer-specific metabolic alteration.
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Affiliation(s)
- Massimiliano Agostini
- Department Experimental Medicine, University of Rome "Tor Vergata", TOR, Via Montpellier,1, 00133, Rome, Italy
| | - Mara Mancini
- IDI-IRCCS, Via Monti di Creta 104, 00166, Rome, Italy
| | - Eleonora Candi
- Department Experimental Medicine, University of Rome "Tor Vergata", TOR, Via Montpellier,1, 00133, Rome, Italy. .,IDI-IRCCS, Via Monti di Creta 104, 00166, Rome, Italy.
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27
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The role of metabolic reprogramming in cancer metastasis and potential mechanism of traditional Chinese medicine intervention. Biomed Pharmacother 2022; 153:113376. [DOI: 10.1016/j.biopha.2022.113376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 11/22/2022] Open
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28
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Agnoletto C, Volinia S. Mitochondria dysfunction in circulating tumor cells. Front Oncol 2022; 12:947479. [PMID: 35992829 PMCID: PMC9386562 DOI: 10.3389/fonc.2022.947479] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/11/2022] [Indexed: 12/16/2022] Open
Abstract
Circulating tumor cells (CTCs) represent a subset of heterogeneous cells, which, once released from a tumor site, have the potential to give rise to metastasis in secondary sites. Recent research focused on the attempt to detect and characterize these rare cells in the circulation, and advancements in defining their molecular profile have been reported in diverse tumor species, with potential implications for clinical applications. Of note, metabolic alterations, involving mitochondria, have been implicated in the metastatic process, as key determinants in the transition of tumor cells to a mesenchymal or stemness-like phenotype, in drug resistance, and in induction of apoptosis. This review aimed to briefly analyse the most recent knowledge relative to mitochondria dysfunction in CTCs, and to envision implications of altered mitochondria in CTCs for a potential utility in clinics.
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Affiliation(s)
- Chiara Agnoletto
- Rete Oncologica Veneta (ROV), Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Stefano Volinia
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Biological and Chemical Research Centre (CNBCh UW), University of Warsaw, Warsaw, Poland
- Center of New Technologies, University of Warsaw, Warsaw, Poland
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29
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Uen W, Tseng T, Wu CP, Lee S. Detachment stress mediated bioenergetic switch of malignant melanoma cells into anti-Warburg phenotype. Aging (Albany NY) 2022; 14:5511-5522. [PMID: 35802540 PMCID: PMC9320547 DOI: 10.18632/aging.204164] [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: 04/05/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022]
Abstract
One of the biological features of cancer cells is their aerobic glycolysis by extensive glucose fermentation to harvest energy, so called Warburg effect. Melanoma is one of the most aggressive human cancers with poor prognosis and high mortality for its high metastatic ability. During the metastatic process, the metastatic tumor cells should survive under detachment stress. However, whether the detachment stress could affect the tumor phenotype is worthy to investigate. We had established the cell model of human melanoma cells under detachment stress, which mimicked circulating melanoma. It had been demonstrated that the detachment stress altered melanoma cell activities, malignancy, and drug sensitivity. In this study, we found that adherent melanoma cells were more sensitive to glucose depletion. Gene expression profiling altered expressions of transporters associated with glucose metabolism. In addition, detachment stress reduced lactate secretion owing to the reduced MCT4 and GLUT1 expressions, the altered glycolytic and respiratory capacities, and the increased superoxide production. Detachment stress also increases the sensitivity of melanoma cells toward the blockade of electron transport chains. Investigation of the change in glucose metabolism of melanoma cells under detachment stress would be critical to provide a novel molecular mechanism to develop potential therapeutics.
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Affiliation(s)
- WuChing Uen
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan.,Department of Hematology and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin, Taipei City, Taiwan
| | - TingTing Tseng
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
| | - Ching-Po Wu
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
| | - ShaoChen Lee
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
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30
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Sanati M, Afshari AR, Kesharwani P, Sukhorukov VN, Sahebkar A. Recent trends in the application of nanoparticles in cancer therapy: The involvement of oxidative stress. J Control Release 2022; 348:287-304. [PMID: 35644289 DOI: 10.1016/j.jconrel.2022.05.035] [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: 03/18/2022] [Revised: 05/17/2022] [Accepted: 05/21/2022] [Indexed: 12/15/2022]
Abstract
In the biomedical area, the interdisciplinary field of nanotechnology has the potential to bring numerous unique applications, including better tactics for cancer detection, diagnosis, and therapy. Nanoparticles (NPs) have been the topic of many research and material applications throughout the last decade. Unlike small-molecule medications, NPs are defined by distinct physicochemical characteristics, such as a large surface-to-volume ratio, which allows them to permeate live cells with relative ease. The versatility of NPs as both therapeutics and diagnostics makes them ideal for a broad spectrum of illnesses, from infectious diseases to cancer. A significant amount of data has been participated in the current scientific publications, emphasizing the concept that NPs often produce reactive oxygen species (ROS) to a larger degree than micro-sized particles. It is important to note that oxidative stress governs a wide range of cell signaling cascades, many of which are responsible for cancer cell cytotoxicity. Here, we aimed to provide insight into the signaling pathways triggered by oxidative stress in cancer cells in response to several types of nanomaterials, such as metallic and polymeric NPs and quantum dots. We discuss recent advances in developing integrated anticancer medicines based on NPs targeted to destroy malignant cells by increasing their ROS setpoint.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran; Experimental and Animal Study Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Vasily N Sukhorukov
- Avtsyn Research Institute of Human Morphology of FSBI "Petrovsky National Research Centre of Surgery", Moscow, Russia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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31
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Cadmium-induced splenic lymphocytes anoikis is not mitigated by activating Nrf2-mediated antioxidative defense response. J Inorg Biochem 2022; 234:111882. [DOI: 10.1016/j.jinorgbio.2022.111882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/19/2022] [Accepted: 05/28/2022] [Indexed: 12/12/2022]
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PDK4 Constitutes a Novel Prognostic Biomarker and Therapeutic Target in Gastric Cancer. Diagnostics (Basel) 2022; 12:diagnostics12051101. [PMID: 35626257 PMCID: PMC9139696 DOI: 10.3390/diagnostics12051101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/05/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and deadly malignancies worldwide. We aimed to assess the functional role and clinical significance of pyruvate dehydrogenase kinase (PDK) in GC and explored the underlying mechanisms. The bioinformatics method was used to investigate the expression of PDKs in GC, the effect on clinical outcomes, enriched pathways, interactive network, and the correlation between PDK4 and immune infiltration. Next, PDK expression in the GC cells and tissues were verified by qRT-PCR and western blotting. A Cell Counting Kit-8 (CCK8), colony-formation, Flow cytometry, Transwell and wound healing assays were carried out to evaluate the influence of PDK4 on cell proliferation, invasion and migration. Among PDKs, PDK4 expression was aberrant in GC and identified as an independent prognostic factor. GO analysis, GSEA, and PPI showed that PDK4 expression may regulate cell adhesion, metal ion transport, synaptic activity, and cancer cell metabolism in GC. Analyses of immune infiltration showed that PDK4 correlated with the abundant expression of various immunocytes. Finally, we verified that upregulation of PDK4 expression enhanced the ability of GC cells to proliferate, migrate, and invade. In conclusion, PDK4 was identified as a potential candidate diagnostic biomarker and therapeutic target for GC patients.
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33
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Xing F, Hu Q, Qin Y, Xu J, Zhang B, Yu X, Wang W. The Relationship of Redox With Hallmarks of Cancer: The Importance of Homeostasis and Context. Front Oncol 2022; 12:862743. [PMID: 35530337 PMCID: PMC9072740 DOI: 10.3389/fonc.2022.862743] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 03/16/2022] [Indexed: 12/18/2022] Open
Abstract
Redox homeostasis is a lifelong pursuit of cancer cells. Depending on the context, reactive oxygen species (ROS) exert paradoxical effects on cancers; an appropriate concentration stimulates tumorigenesis and supports the progression of cancer cells, while an excessive concentration leads to cell death. The upregulated antioxidant system in cancer cells limits ROS to a tumor-promoting level. In cancers, redox regulation interacts with tumor initiation, proliferation, metastasis, programmed cell death, autophagy, metabolic reprogramming, the tumor microenvironment, therapies, and therapeutic resistance to facilitate cancer development. This review discusses redox control and the major hallmarks of cancer.
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Affiliation(s)
- Faliang Xing
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qiangsheng Hu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- *Correspondence: Wei Wang, ; Xianjun Yu, ; Bo Zhang,
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- *Correspondence: Wei Wang, ; Xianjun Yu, ; Bo Zhang,
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- *Correspondence: Wei Wang, ; Xianjun Yu, ; Bo Zhang,
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Loric S, Conti M. Versatile Functional Energy Metabolism Platform Working From Research to Patient: An Integrated View of Cell Bioenergetics. FRONTIERS IN TOXICOLOGY 2022; 3:750431. [PMID: 35295105 PMCID: PMC8915814 DOI: 10.3389/ftox.2021.750431] [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: 07/30/2021] [Accepted: 10/08/2021] [Indexed: 12/06/2022] Open
Abstract
Mitochondrial dysfunctions that were not discovered during preclinical and clinical testing have been responsible for at least restriction of use as far as withdrawal of many drugs. To solve mitochondrial machinery complexity, integrative methodologies combining different data, coupled or not to mathematic modelling into systems biology, could represent a strategic way but are still very hard to implement. These technologies should be accurate and precise to avoid accumulation of errors that can lead to misinterpretations, and then alter prediction efficiency. To address such issue, we have developed a versatile functional energy metabolism platform that can measure quantitatively, in parallel, with a very high precision and accuracy, a high number of biological parameters like substrates or enzyme cascade activities in essential metabolism units (glycolysis, respiratory chain ATP production, oxidative stress...) Its versatility (our platform works on either cell lines or small animals and human samples) allows cell metabolism pathways fine tuning comparison from preclinical to clinical studies. Applied here to OXPHOS and/or oxidative stress as an example, it allows discriminating compounds with acute toxic effects but, most importantly, those inducing low noise chronic ones.
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Obata F, Ozuru R, Tsuji T, Matsuba T, Fujii J. Stx2 Induces Differential Gene Expression and Disturbs Circadian Rhythm Genes in the Proximal Tubule. Toxins (Basel) 2022; 14:toxins14020069. [PMID: 35202097 PMCID: PMC8874938 DOI: 10.3390/toxins14020069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/04/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
Shiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. We determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression in the proximal tubules. Stx2-injected mouse kidney tissues and Stx2-treated human primary renal proximal tubular epithelial cell (RPTEC) were collected and microarray analysis was performed. We compared murine kidney and RPTEC arrays and selected common 58 genes that are differentially expressed vs. control (0 h, no toxin-treated). We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Genes associated with previously reported Stx2 activities such as src kinase Yes phosphorylation pathway activation, unfolded protein response (UPR) and ribotoxic stress response (RSR) showed differential expressions. Moreover, circadian clock genes were differentially expressed, suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1 (SLC5A1) was down-regulated, indicating proximal tubular functional deterioration, and mice developed glucosuria confirming proximal tubular dysfunction. Stx2 alters gene expression in murine and human proximal tubules through known activities and newly investigated circadian rhythm disturbance, which may result in proximal tubular dysfunctions.
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Affiliation(s)
- Fumiko Obata
- Division of Bacteriology, Department of Microbiology and Immunology, Faculty of Medicine, Tottori University, 86 Nishicho, Yonago 683-8503, Japan; (T.T.); (J.F.)
- Correspondence:
| | - Ryo Ozuru
- Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan;
| | - Takahiro Tsuji
- Division of Bacteriology, Department of Microbiology and Immunology, Faculty of Medicine, Tottori University, 86 Nishicho, Yonago 683-8503, Japan; (T.T.); (J.F.)
| | - Takashi Matsuba
- Division of Infectious Disease Control and Prevention, Department of Animal Pharmaceutical Science, School of Pharmaceutical Science, Kyusyu University of Health and Welfare, 1714-1 Yoshino-machi, Nobeoka 882-8508, Japan;
| | - Jun Fujii
- Division of Bacteriology, Department of Microbiology and Immunology, Faculty of Medicine, Tottori University, 86 Nishicho, Yonago 683-8503, Japan; (T.T.); (J.F.)
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HBXIP induces anoikis resistance by forming a reciprocal feedback loop with Nrf2 to maintain redox homeostasis and stabilize Prdx1 in breast cancer. NPJ Breast Cancer 2022; 8:7. [PMID: 35027562 PMCID: PMC8758767 DOI: 10.1038/s41523-021-00374-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 12/07/2021] [Indexed: 12/12/2022] Open
Abstract
Anoikis resistance is an essential prerequisite for tumor metastasis, but the underlying molecular mechanisms remain unknown. Herein, we report that the oncoprotein hepatitis B X-interacting protein (HBXIP) is prominently upregulated in breast cancer cells following ECM detachment. Altering HBXIP expression can impair the anchorage-independent growth ability of tumor cells. Mechanistically, HBXIP, which binds to Kelch-like ECH-associated protein 1 (Keap1) to activate nuclear factor E2-related factor 2 (Nrf2), contains a cis-acting antioxidant response element (ARE) in the gene promoter and is a target gene of Nrf2. The HBXIP/Nrf2 axis forms a reciprocal positive feedback loop that reinforces the expression and tumor-promoting actions of each protein. In response to ECM detachment, Nrf2 reduces reactive oxygen species (ROS) accumulation, protects the mitochondrial membrane potential and increases cellular ATP, GSH and NADPH levels to maintain breast cancer cell survival. Meanwhile, the reinforcement of HBXIP induced by Nrf2 inhibits JNK1 activation by inhibiting ubiquitin-mediated degradation of Prdx1, which also plays an essential role in promoting ECM-detached cell survival. Furthermore, a strong positive correlation was identified between HBXIP expression and Prdx1 expression in clinical breast cancer tissues and TCGA Pan-Cancer Atlas clinical data of breast invasive carcinoma based on the cBioPortal cancer genomics database. Co-expression of HBXIP and Prdx1 predicts a poor prognosis for breast cancer patients. Collectively, our findings reveal a significant mechanism by which the HBXIP/Nrf2 feedback loop contributes to anoikis resistance by maintaining redox homeostasis and inhibiting JNK1 activation and support the likely therapeutic value of the HBXIP/Nrf2 axis in breast cancer patients.
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Adeshakin FO, Adeshakin AO, Liu Z, Cheng J, Zhang P, Yan D, Zhang G, Wan X. Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis. Life (Basel) 2021; 12:life12010042. [PMID: 35054435 PMCID: PMC8779336 DOI: 10.3390/life12010042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/30/2022] Open
Abstract
Metastasis arises owing to tumor cells’ capacity to evade pro-apoptotic signals. Anoikis—the apoptosis of detached cells (from the extracellular matrix (ECM)) is often circumvented by metastatic cells as a result of biochemical and molecular transformations. These facilitate cells’ ability to survive, invade and reattach to secondary sites. Here, we identified deregulated glucose metabolism, oxidative phosphorylation, and proteasome in anchorage-independent cells compared to adherent cells. Metformin an anti-diabetic drug that reduces blood glucose (also known to inhibit mitochondrial Complex I), and proteasome inhibitors were employed to target these changes. Metformin or proteasome inhibitors alone increased misfolded protein accumulation, sensitized tumor cells to anoikis, and impaired pulmonary metastasis in the B16F10 melanoma model. Mechanistically, metformin reduced cellular ATP production, activated AMPK to foster pro-apoptotic unfolded protein response (UPR) through enhanced expression of CHOP in ECM detached cells. Furthermore, AMPK inhibition reduced misfolded protein accumulation, thus highlight relevance of AMPK activation in facilitating metformin-induced stress and UPR cell death. Our findings provide insights into the molecular biology of anoikis resistance and identified metformin and proteasome inhibitors as potential therapeutic options for tumor metastasis.
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Affiliation(s)
- Funmilayo O. Adeshakin
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
- University of Chinese Academy of Sciences, Beijing 100864, China
| | - Adeleye O. Adeshakin
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
- University of Chinese Academy of Sciences, Beijing 100864, China
| | - Zhao Liu
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
| | - Jian Cheng
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
| | - Pengchao Zhang
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
- University of Chinese Academy of Sciences, Beijing 100864, China
| | - Dehong Yan
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
- University of Chinese Academy of Sciences, Beijing 100864, China
| | - Guizhong Zhang
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
- Correspondence: (G.Z.); (X.W.)
| | - Xiaochun Wan
- Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (F.O.A.); (A.O.A.); (Z.L.); (J.C.); (P.Z.); (D.Y.)
- University of Chinese Academy of Sciences, Beijing 100864, China
- Correspondence: (G.Z.); (X.W.)
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Mu J, Tian Y, Liu F, Wang Z, Tan R, Zhang B, Quan P, Zhang H, Yang J, Yuan P. Mitochondrial transcription factor B1 promotes the progression of hepatocellular carcinoma via enhancing aerobic glycolysis. J Cell Commun Signal 2021; 16:223-238. [PMID: 34825289 DOI: 10.1007/s12079-021-00658-8] [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: 09/08/2021] [Accepted: 11/09/2021] [Indexed: 12/27/2022] Open
Abstract
Mitochondrial dysfunctions play crucial roles in the carcinogenesis of various human cancers. However, the molecular mechanisms leading to mitochondrial dysfunction and thus cancer progression remains largely unclear. TFB1M (mitochondrial transcription factor B1) is a mitochondrial DNA-binding protein that activates the transcription of mitochondrial DNA. Our bioinformatics analysis indicated a significant up-regulation of TFB1M in hepatocellular carcinoma (HCC). Here, we investigated its clinical significance and biological functions in this malignancy. Here, we found that TFB1M was significantly upregulated in HCC cells probably due to decreased miR-130a-3p expression. High TFB1M expression was positively associated with poor patient survival in HCC. TFB1M contributes to HCC growth and metastasis by promoting cell cycle progression, epithelia-mesenchymal transition (EMT), and inhibiting cell apoptosis. Mechanistically, the metabolic switch from oxidative phosphorylation to glycolysis contributed to the promotion of tumor growth and metastasis by TFB1M overexpression in HCC cells. In summary, we demonstrate that TFB1M plays a crucial oncogenic role in HCC progression, indicating TFB1M as a promising prognostic marker and therapeutic target in HCC.
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Affiliation(s)
- Jiao Mu
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China.,Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.,Department of Hematology, Xi'an Central Hospital, Xi'an, 710003, Shaanxi, China
| | - Yiyuan Tian
- Physiology Divion of Yan'an University Medical College, Yan'an, 716000, Shaanxi, China
| | - Fengzhou Liu
- Aerospace Clinical Medical Center, School of Aerospace Medicine, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Zijun Wang
- Battalion of the First Regiment of Cadets of Basic Medicine, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Rui Tan
- Department of Orthopaedics, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Bei Zhang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China
| | - Penghe Quan
- Department of Urology, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hongxin Zhang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China.
| | - Jingyue Yang
- Department of Oncology, Xijing Hospital, Air Force Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
| | - Peng Yuan
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China. .,State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
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Choudhury FK. Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression. Antioxidants (Basel) 2021; 10:antiox10111838. [PMID: 34829708 PMCID: PMC8615124 DOI: 10.3390/antiox10111838] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/20/2022] Open
Abstract
Mitochondrial redox metabolism is the central component in the cellular metabolic landscape, where anabolic and catabolic pathways are reprogrammed to maintain optimum redox homeostasis. During different stages of cancer, the mitochondrial redox status plays an active role in navigating cancer cells’ progression and regulating metabolic adaptation according to the constraints of each stage. Mitochondrial reactive oxygen species (ROS) accumulation induces malignant transformation. Once vigorous cell proliferation renders the core of the solid tumor hypoxic, the mitochondrial electron transport chain mediates ROS signaling for bringing about cellular adaptation to hypoxia. Highly aggressive cells are selected in this process, which are capable of progressing through the enhanced oxidative stress encountered during different stages of metastasis for distant colonization. Mitochondrial oxidative metabolism is suppressed to lower ROS generation, and the overall cellular metabolism is reprogrammed to maintain the optimum NADPH level in the mitochondria required for redox homeostasis. After reaching the distant organ, the intrinsic metabolic limitations of that organ dictate the success of colonization and flexibility of the mitochondrial metabolism of cancer cells plays a pivotal role in their adaptation to the new environment.
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Affiliation(s)
- Feroza K Choudhury
- Drug Metabolism and Pharmacokinetics Department, Genentech Inc., South San Francisco, CA 94080, USA
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40
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Castelli S, De Falco P, Ciccarone F, Desideri E, Ciriolo MR. Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison. Cancers (Basel) 2021; 13:cancers13215484. [PMID: 34771647 PMCID: PMC8583096 DOI: 10.3390/cancers13215484] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/28/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022] Open
Abstract
Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.
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Affiliation(s)
- Serena Castelli
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy; (S.C.); (P.D.F.); (E.D.)
| | - Pamela De Falco
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy; (S.C.); (P.D.F.); (E.D.)
| | - Fabio Ciccarone
- IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Enrico Desideri
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy; (S.C.); (P.D.F.); (E.D.)
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome “Tor Vergata”, Via Della Ricerca Scientifica 1, 00133 Rome, Italy; (S.C.); (P.D.F.); (E.D.)
- IRCCS San Raffaele Pisana, Via Della Pisana 235, 00163 Rome, Italy
- Correspondence:
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41
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Bisht VS, Giri K, Kumar D, Ambatipudi K. Oxygen and metabolic reprogramming in the tumor microenvironment influences metastasis homing. Cancer Biol Ther 2021; 22:493-512. [PMID: 34696706 DOI: 10.1080/15384047.2021.1992233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Tumor metastasis is the leading cause of cancer mortality, often characterized by abnormal cell growth and invasion to distant organs. The cancer invasion due to epithelial to mesenchymal transition is affected by metabolic and oxygen availability in the tumor-associated micro-environment. A precise alteration in oxygen and metabolic signaling between healthy and metastatic cells is a substantial probe for understanding tumor progression and metastasis. Molecular heterogeneity in the tumor microenvironment help to sustain the metastatic cell growth during their survival shift from low to high metabolic-oxygen-rich sites and reinforces the metastatic events. This review highlighted the crucial role of oxygen and metabolites in metastatic progression and exemplified the role of metabolic rewiring and oxygen availability in cancer cell adaptation. Furthermore, we have also addressed potential applications of altered oxygen and metabolic networking with tumor type that could be a signature pattern to assess tumor growth and chemotherapeutics efficacy in managing cancer metastasis.
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Affiliation(s)
- Vinod S Bisht
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India
| | - Kuldeep Giri
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India
| | - Deepak Kumar
- Department of Cancer Biology, Central Drug Research Institute, Lucknow, India.,Academy of Scientific & Innovative Research, New Delhi, India
| | - Kiran Ambatipudi
- Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India
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42
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Mucci A, Antonarelli G, Caserta C, Vittoria FM, Desantis G, Pagani R, Greco B, Casucci M, Escobar G, Passerini L, Lachmann N, Sanvito F, Barcella M, Merelli I, Naldini L, Gentner B. Myeloid cell-based delivery of IFN-γ reprograms the leukemia microenvironment and induces anti-tumoral immune responses. EMBO Mol Med 2021; 13:e13598. [PMID: 34459560 PMCID: PMC8495462 DOI: 10.15252/emmm.202013598] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that interferon-γ (IFN-γ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity depended on the immune system's capacity to respond to IFN-γ and drove the counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFN-γ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFN-γ was further enhanced by either co-delivery of tumor necrosis factor-α (TNF-α) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.
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Affiliation(s)
- Adele Mucci
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
| | - Gabriele Antonarelli
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
- Vita‐Salute San Raffaele UniversityMilanItaly
| | - Carolina Caserta
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
| | - Francesco Maria Vittoria
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
- Vita‐Salute San Raffaele UniversityMilanItaly
| | - Giacomo Desantis
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
| | - Riccardo Pagani
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
- Vita‐Salute San Raffaele UniversityMilanItaly
| | - Beatrice Greco
- Innovative Immunotherapies UnitDivision of Immunology, Transplantation, and Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly
| | - Monica Casucci
- Innovative Immunotherapies UnitDivision of Immunology, Transplantation, and Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly
| | - Giulia Escobar
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
| | - Laura Passerini
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
| | - Nico Lachmann
- Department of Pediatric Pneumology, Allergology and NeonatologyHannover Medical SchoolHannoverGermany
| | | | - Matteo Barcella
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
- National Research CouncilInstitute for Biomedical TechnologiesSegrateItaly
| | - Ivan Merelli
- National Research CouncilInstitute for Biomedical TechnologiesSegrateItaly
| | - Luigi Naldini
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
- Vita‐Salute San Raffaele UniversityMilanItaly
| | - Bernhard Gentner
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS San Raffaele Scientific InstituteMilanItaly
- Hematology and Bone Marrow Transplantation UnitIRCCS San Raffaele HospitalMilanItaly
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43
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Somarribas Patterson LF, Vardhana SA. Metabolic regulation of the cancer-immunity cycle. Trends Immunol 2021; 42:975-993. [PMID: 34610889 DOI: 10.1016/j.it.2021.09.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 12/11/2022]
Abstract
The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies.
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Affiliation(s)
- Luis F Somarribas Patterson
- Department of Biochemistry, School of Medicine, University of Costa Rica, 11501-2060 San José, Costa Rica; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Santosha A Vardhana
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
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44
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Abstract
Metabolism is an important part of tumorigenesis as well as progression. The various cancer metabolism pathways, such as glucose metabolism and glutamine metabolism, directly regulate the development and progression of cancer. The pathways by which the cancer cells rewire their metabolism according to their needs, surrounding environment and host tissue conditions are an important area of study. The regulation of these metabolic pathways is determined by various oncogenes, tumor suppressor genes, as well as various constituent cells of the tumor microenvironment. Expanded studies on metabolism will help identify efficient biomarkers for diagnosis and strategies for therapeutic interventions and countering ways by which cancers may acquire resistance to therapy.
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45
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Sellitto A, Pecoraro G, Giurato G, Nassa G, Rizzo F, Saggese P, Martinez CA, Scafoglio C, Tarallo R. Regulation of Metabolic Reprogramming by Long Non-Coding RNAs in Cancer. Cancers (Basel) 2021; 13:cancers13143485. [PMID: 34298698 PMCID: PMC8308086 DOI: 10.3390/cancers13143485] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 01/10/2023] Open
Abstract
Metabolic reprogramming is a well described hallmark of cancer. Oncogenic stimuli and the microenvironment shape the metabolic phenotype of cancer cells, causing pathological modifications of carbohydrate, amino acid and lipid metabolism that support the uncontrolled growth and proliferation of cancer cells. Conversely, metabolic alterations in cancer can drive changes in genetic programs affecting cell proliferation and differentiation. In recent years, the role of non-coding RNAs in metabolic reprogramming in cancer has been extensively studied. Here, we review this topic, with a focus on glucose, glutamine, and lipid metabolism and point to some evidence that metabolic alterations occurring in cancer can drive changes in non-coding RNA expression, thus adding an additional level of complexity in the relationship between metabolism and genetic programs in cancer cells.
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Affiliation(s)
- Assunta Sellitto
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Pasquale Saggese
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Cesar A. Martinez
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Claudio Scafoglio
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
- Correspondence: ; Tel.: +39-089-965067
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McCann C, Kerr EM. Metabolic Reprogramming: A Friend or Foe to Cancer Therapy? Cancers (Basel) 2021; 13:3351. [PMID: 34283054 PMCID: PMC8267696 DOI: 10.3390/cancers13133351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022] Open
Abstract
Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical "cell death" machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.
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Affiliation(s)
| | - Emma M. Kerr
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, 97 Lisburn Rd, BT9 7AE Belfast, Ireland;
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Kim CJ, Terado T, Tambe Y, Mukaisho KI, Kageyama S, Kawauchi A, Inoue H. Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. Int J Oncol 2021; 59:40. [PMID: 33982789 PMCID: PMC8131085 DOI: 10.3892/ijo.2021.5220] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three‑dimensional (3D)‑spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D‑spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β‑catenin, as well as the expression of N‑cadherin, which are all critical for inducing epithelial‑mesenchymal transition (EMT). The knockdown of β‑catenin or PDK4 using specific small interfering RNAs suppressed N‑cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β‑catenin and N‑cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT‑2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β‑catenin expression in CPT‑treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β‑catenin/N‑cadherin pathway.
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Affiliation(s)
- Chul Jang Kim
- Department of Urology, Kohka Public Hospital, Minakuchi-cho, Kohka, Shiga 528-0074, Japan
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Tokio Terado
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Yukihiro Tambe
- Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Ken-Ichi Mukaisho
- Division of Human Pathology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Susumu Kageyama
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Akihiro Kawauchi
- Department of Urology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Hirokazu Inoue
- Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
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48
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Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis. Cell Death Dis 2021; 12:629. [PMID: 34145217 PMCID: PMC8213763 DOI: 10.1038/s41419-021-03890-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023]
Abstract
Detachment is the initial and critical step for cancer metastasis. Only the cells that survive from detachment can develop metastases. Following the disruption of cell-extracellular matrix (ECM) interactions, cells are exposed to a totally different chemical and mechanical environment. During which, cells inevitably suffer from multiple stresses, including loss of growth stimuli from ECM, altered mechanical force, cytoskeletal reorganization, reduced nutrient uptake, and increased reactive oxygen species generation. Here we review the impact of these stresses on the anchorage-independent survival and the underlying molecular signaling pathways. Furthermore, its implications in cancer metastasis and treatment are also discussed.
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Adeshakin FO, Adeshakin AO, Liu Z, Lu X, Cheng J, Zhang P, Yan D, Zhang G, Wan X. Upregulation of V-ATPase by STAT3 Activation Promotes Anoikis Resistance and Tumor Metastasis. J Cancer 2021; 12:4819-4829. [PMID: 34234852 PMCID: PMC8247373 DOI: 10.7150/jca.58670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
Most cancer mortality results from metastatic tumor cells and not the localized tumor. Overcoming anoikis is one of the most important steps for detached tumor cells to migrate and metastasize. However, the molecular mechanisms remain to be fully deciphered. Herein, our study revealed upregulation of vacuolar ATPase (V-ATPase) in cancer cells during ECM detachment plays a key role in anoikis evasion. V-ATPase is an enzyme complex that utilizes energy from ATP hydrolysis to maintain cellular homeostasis and had been reported to enhance cancer progression. In this study, V-ATPase inhibition sensitized human cervical cancer, breast cancer, and murine melanoma cells to anoikis via increased ROS production, accumulation of misfolded protein, and impaired pulmonary metastasis in vivo. Scavenging ROS restored anoikis resistance and clearance of misfolded protein accumulation in the tumor cells. Mechanistically, STAT3 upregulates V-ATPase expression while blockade of STAT3 activity repressed V-ATPase expression in these tumor cells as well as sensitized cells to anoikis, increased ROS production, and misfolded protein accumulation. Altogether, our data demonstrate an unreported role of STAT3 in mediating the upregulation of V-ATPase to promote anoikis resistance, thus provides an alternative option to target cancer metastasis.
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Affiliation(s)
- Funmilayo O Adeshakin
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,University of Chinese Academy of Sciences, Beijing, 100864, China
| | - Adeleye O Adeshakin
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,University of Chinese Academy of Sciences, Beijing, 100864, China
| | - Zhao Liu
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Xiaoxu Lu
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,University of Chinese Academy of Sciences, Beijing, 100864, China
| | - Jian Cheng
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,School of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121000, China
| | - Pengchao Zhang
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,University of Chinese Academy of Sciences, Beijing, 100864, China
| | - Dehong Yan
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,University of Chinese Academy of Sciences, Beijing, 100864, China
| | - Guizhong Zhang
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Xiaochun Wan
- Guangdong Immune Cell therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,University of Chinese Academy of Sciences, Beijing, 100864, China
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Oxidative Stress in Cancer Cell Metabolism. Antioxidants (Basel) 2021; 10:antiox10050642. [PMID: 33922139 PMCID: PMC8143540 DOI: 10.3390/antiox10050642] [Citation(s) in RCA: 272] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/10/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022] Open
Abstract
Reactive oxygen species (ROS) are important in regulating normal cellular processes whereas deregulated ROS leads to the development of a diseased state in humans including cancers. Several studies have been found to be marked with increased ROS production which activates pro-tumorigenic signaling, enhances cell survival and proliferation and drives DNA damage and genetic instability. However, higher ROS levels have been found to promote anti-tumorigenic signaling by initiating oxidative stress-induced tumor cell death. Tumor cells develop a mechanism where they adjust to the high ROS by expressing elevated levels of antioxidant proteins to detoxify them while maintaining pro-tumorigenic signaling and resistance to apoptosis. Therefore, ROS manipulation can be a potential target for cancer therapies as cancer cells present an altered redox balance in comparison to their normal counterparts. In this review, we aim to provide an overview of the generation and sources of ROS within tumor cells, ROS-associated signaling pathways, their regulation by antioxidant defense systems, as well as the effect of elevated ROS production in tumor progression. It will provide an insight into how pro- and anti-tumorigenic ROS signaling pathways could be manipulated during the treatment of cancer.
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