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Pandey A, Goswami A, Jithin B, Shukla S. Autophagy: The convergence point of aging and cancer. Biochem Biophys Rep 2025; 42:101986. [PMID: 40224538 PMCID: PMC11986642 DOI: 10.1016/j.bbrep.2025.101986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/10/2025] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Autophagy, a dynamic intracellular degradation system, is critical for cellular renovation and maintaining equilibrium. By eliminating damaged components and recycling essential molecules, autophagy safeguards cellular integrity and function. The versatility of the autophagy process across various biological functions enable cells to adapt and maintain homeostasis under unfavourable conditions. Disruptions in autophagy can shift a cell from a healthy state to a disease state or, conversely, support a return to health. This review delves into the multifaceted role of autophagy during aging and age-related diseases such as cancer, highlighting its significance as a unifying target with promising therapeutic implications. Cancer development is a dynamic process characterized by the acquisition of diverse survival capabilities for proliferating at different stages. This progression unfolds over time, with cancer cells exploiting autophagy to overcome encountered stress conditions during tumor development. Notably, there are several common pathways that utilize the autophagy process during aging and cancer development. This highlights the importance of autophagy as a crucial therapeutic target, holding the potential to not only impede the growth of tumor but also enhance the patient's longevity. This review aims to simplify the intricate relationship between cancer and aging, with a particular focus on the role of autophagy.
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Affiliation(s)
- Anchala Pandey
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh, 462066, India
| | | | | | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh, 462066, India
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2
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de la Peña A, Retamal C, Pérez-Molina F, Díaz-Valdivia N, Veloso-Bahamondes F, Tapia D, Cancino J, Randow F, González A, Oyanadel C, Soza A. Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation. Eur J Cell Biol 2025; 104:151488. [PMID: 40209344 DOI: 10.1016/j.ejcb.2025.151488] [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: 11/26/2024] [Revised: 03/21/2025] [Accepted: 03/30/2025] [Indexed: 04/12/2025] Open
Abstract
Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes cell proliferation by transactivating the EGFR-ERK signaling pathway, is overexpressed in several cancers. However, its impact on mitochondrial dynamics during cell proliferation remains unknown. Using MDCK and RPTEC kidney epithelial cells, we demonstrate that Gal-8 induces mitochondrial fragmentation and perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, and live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK signaling inhibition abrogates all these Gal-8-induced mitochondrial changes and cell proliferation. Studies with established mutant versions of Gal-8 and CHO cells reveal that mitochondrial changes and proliferative response require interactions between the N-terminal carbohydrate recognition domain of Gal-8 and α-2,3-sialylated N-glycans at the cell surface. DRP1, a key regulator of mitochondrial fission, becomes phosphorylated in MDCK cells or overexpressed in RPTEC cells in an ERK-dependent manner, mediating mitochondrial fragmentation and perinuclear redistribution. Bafilomycin A abrogates Gal-8-induced cell proliferation, suggesting that mitophagy serves as an adaptation to cell proliferation demands. Functional analysis under Gal-8 stimulation shows that mitochondria maintain an active electron transport chain, partially uncoupled from ATP synthesis, and an increased membrane potential, indicative of healthy mitochondria. Meanwhile, the cells exhibit increased extracellular acidification rate and lactate production via aerobic glycolysis, a hallmark of an active proliferative state. Our findings integrate mitochondrial dynamics with metabolic adaptations during Gal-8-induced cell proliferation, with potential implications for physiology, disease, and therapeutic strategies.
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Affiliation(s)
- Adely de la Peña
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Claudio Retamal
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Departamento de Ciencias Biológicas y Químicas, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Francisca Pérez-Molina
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Nicole Díaz-Valdivia
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Francisco Veloso-Bahamondes
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Diego Tapia
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Jorge Cancino
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Felix Randow
- Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, UK; Department of Medicine, University of Cambridge, UK
| | - Alfonso González
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad San Sebastián, Santiago, Chile; Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
| | - Claudia Oyanadel
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Departamento de Ciencias Biológicas y Químicas, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile.
| | - Andrea Soza
- Centro de Biología Celular y Biomedicina, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
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Min DH, Kim D, Hong ST, Kim J, Kim MJ, Kwon SH, Kim A, Lee JY. Bafilomycin A1 induces colon cancer cell death through impairment of the endolysosome system dependent on iron. Sci Rep 2025; 15:5148. [PMID: 39934167 PMCID: PMC11814099 DOI: 10.1038/s41598-025-89127-5] [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: 10/11/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
The late endolysosomal compartment plays a crucial role in cancer cell metabolism by regulating lysosomal activity, essential for cell proliferation, and the degradation of cellular components during the final stages of autophagy. Modulating late endolysosomal function represents a new target for cancer therapy. In this study, we investigated the effects of bafilomycin A1 (BA1), a vacuolar H+-ATPase inhibitor, on colon cancer and normal colon fibroblasts (CCD-18Co) cells. We found that very low concentrations (~ 2 nM) of BA1 selectively induced cell death in colon cancer cells. This cytotoxicity was associated with lysosomal stress response and dysregulation of iron homeostasis. BA1 treatment resulted in significant alterations to the endolysosomal system, including an increased number and size of lysosomes, lysosomal membrane permeabilization, and autophagy flux blockade. These changes were accompanied by endoplasmic reticulum stress and lipid droplet accumulation. Furthermore, BA1 decreased intracellular Fe2+ levels, as measured using FerroOrange. Notably, iron (III)-citrate supplementation rescued cells from BA1-induced death. These findings suggest that BA1-induced endolysosomal dysfunction impairs iron homeostasis, ultimately leading to colon cancer cell death. Our results highlight the potential of targeting endolysosomal function and iron homeostasis as novel therapeutic strategies for colon cancer, paving the way for more selective and effective treatments.
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Affiliation(s)
- Dong Hwa Min
- Department of Pathology, Korea University College of Medicine, 73, Anan-Dong 5-GA, Seongbuk-gu, Seoul, 02841, South Korea
- Department of Biomedical Science, Korea University College of Medicine, Seoul, 02841, South Korea
| | - Dasom Kim
- Department of Pathology, Korea University College of Medicine, 73, Anan-Dong 5-GA, Seongbuk-gu, Seoul, 02841, South Korea
- Department of Biomedical Science, Korea University College of Medicine, Seoul, 02841, South Korea
| | - Seung Taek Hong
- Division of Biohealthcare, Department of Echo-Applied Chemistry, Daejin University, Pocheon-si, 11159, Gyeonggi-do, South Korea
| | - Joohee Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, South Korea
| | - Min Jung Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, South Korea
| | - Seung-Hae Kwon
- Seoul Center, Korea Basic Science Institute, Seoul, 02841, South Korea
| | - Aeree Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, South Korea
| | - Ji-Yun Lee
- Department of Pathology, Korea University College of Medicine, 73, Anan-Dong 5-GA, Seongbuk-gu, Seoul, 02841, South Korea.
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Rintz E, Ziemian M, Kobus B, Gaffke L, Pierzynowska K, Wegrzyn G. Synergistic effects of resveratrol and enzyme replacement therapy in the Mucopolysaccharidosis type I. Biochem Pharmacol 2024; 229:116467. [PMID: 39111602 DOI: 10.1016/j.bcp.2024.116467] [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: 01/12/2024] [Revised: 08/02/2024] [Accepted: 08/03/2024] [Indexed: 08/13/2024]
Abstract
Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder caused by mutations in the IDUA gene, leading to alpha-L-iduronidase enzyme deficiency and resulting in the accumulation of glycosaminoglycans (GAG; heparan and dermatan sulfate) in lysosomes. The consequent GAG accumulation within cells leads to organ dysfunction and a range of debilitating symptoms. Enzyme replacement therapy (ERT) is the prevailing treatment, but its limitations (including high cost, time requirements, inefficiency in treatment of central nervous system (CNS), and immunogenicity) necessitate exploration of alternative therapeutic strategies. This research propose a novel approach leveraging the synergistic effects of ERT and resveratrol-induced autophagy. Resveratrol, with its immunomodulatory and GAG degradation-stimulating properties, holds a promise in mitigating immune responses triggered by ERT. Moreover, its ability to penetrate the blood-brain barrier presents a potential solution for addressing CNS manifestations. This study employed cells from MPS I patients to investigate the combined effects of resveratrol and the enzyme. Evaluation of the therapeutic impact involved assessing GAG accumulation, enzyme testing, and examining lysosome functionality and the autophagy process through fluorescence microscopy and Western blotting. The combined therapy stimulated the lysosomal mannose-6-phosphate receptor (M6PR) and lysosome biogenesis through the transcription factor EB (TFEB). Additionally, initial block of autophagy in autophagosome formation was relieved after the combined therapy and resveratrol alone. Together with increased enzyme activity through stimulation of the receptor, this synergistic therapy can be considered a new potential treatment for MPS I patients, improving their overall quality of life.
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Affiliation(s)
- Estera Rintz
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland.
| | - Maja Ziemian
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
| | - Barbara Kobus
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
| | - Lidia Gaffke
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
| | - Karolina Pierzynowska
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
| | - Grzegorz Wegrzyn
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland
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Pesti I, Barczánfalvi G, Dulka K, Kata D, Farkas E, Gulya K. Bafilomycin 1A Affects p62/SQSTM1 Autophagy Marker Protein Level and Autophagosome Puncta Formation Oppositely under Various Inflammatory Conditions in Cultured Rat Microglial Cells. Int J Mol Sci 2024; 25:8265. [PMID: 39125836 PMCID: PMC11311604 DOI: 10.3390/ijms25158265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Regulation of autophagy through the 62 kDa ubiquitin-binding protein/autophagosome cargo protein sequestosome 1 (p62/SQSTM1), whose level is generally inversely proportional to autophagy, is crucial in microglial functions. Since autophagy is involved in inflammatory mechanisms, we investigated the actions of pro-inflammatory lipopolysaccharide (LPS) and anti-inflammatory rosuvastatin (RST) in secondary microglial cultures with or without bafilomycin A1 (BAF) pretreatment, an antibiotic that potently inhibits autophagosome fusion with lysosomes. The levels of the microglia marker protein Iba1 and the autophagosome marker protein p62/SQSTM1 were quantified by Western blots, while the number of p62/SQSTM1 immunoreactive puncta was quantitatively analyzed using fluorescent immunocytochemistry. BAF pretreatment hampered microglial survival and decreased Iba1 protein level under all culturing conditions. Cytoplasmic p62/SQSTM1 level was increased in cultures treated with LPS+RST but reversed markedly when BAF+LPS+RST were applied together. Furthermore, the number of p62/SQSTM1 immunoreactive autophagosome puncta was significantly reduced when RST was used but increased significantly in BAF+RST-treated cultures, indicating a modulation of autophagic flux through reduction in p62/SQSTM1 degradation. These findings collectively indicate that the cytoplasmic level of p62/SQSTM1 protein and autophagocytotic flux are differentially regulated, regardless of pro- or anti-inflammatory state, and provide context for understanding the role of autophagy in microglial function in various inflammatory settings.
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Affiliation(s)
- István Pesti
- Department of Cell Biology and Molecular Medicine, University of Szeged, 6720 Szeged, Hungary; (I.P.); (G.B.); (K.D.); (E.F.)
- HCEMM-USZ Group of Cerebral Blood Flow and Metabolism, University of Szeged, 6720 Szeged, Hungary
| | - Gábor Barczánfalvi
- Department of Cell Biology and Molecular Medicine, University of Szeged, 6720 Szeged, Hungary; (I.P.); (G.B.); (K.D.); (E.F.)
| | - Karolina Dulka
- Department of Cell Biology and Molecular Medicine, University of Szeged, 6720 Szeged, Hungary; (I.P.); (G.B.); (K.D.); (E.F.)
| | - Diana Kata
- Department of Laboratory Medicine, University of Szeged, 6725 Szeged, Hungary;
| | - Eszter Farkas
- Department of Cell Biology and Molecular Medicine, University of Szeged, 6720 Szeged, Hungary; (I.P.); (G.B.); (K.D.); (E.F.)
- HCEMM-USZ Group of Cerebral Blood Flow and Metabolism, University of Szeged, 6720 Szeged, Hungary
| | - Karoly Gulya
- Department of Cell Biology and Molecular Medicine, University of Szeged, 6720 Szeged, Hungary; (I.P.); (G.B.); (K.D.); (E.F.)
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Skrzeszewski M, Maciejewska M, Kobza D, Gawrylak A, Kieda C, Waś H. Risk factors of using late-autophagy inhibitors: Aspects to consider when combined with anticancer therapies. Biochem Pharmacol 2024; 225:116277. [PMID: 38740222 DOI: 10.1016/j.bcp.2024.116277] [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: 01/23/2024] [Revised: 04/23/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
Cancer resistance to therapy is still an unsolved scientific and clinical problem. In 2022, the hallmarks of cancer have been expanded to include four new features, including cellular senescence. Therapy-induced senescence (TIS) is a stressor-based response to conventional treatment methods, e.g. chemo- and radiotherapy, but also to non-conventional targeted therapies. Since TIS reinforces resistance in cancers, new strategies for sensitizing cancer cells to therapy are being adopted. These include macroautophagy as a potential target for inhibition due to its potential cytoprotective role in many cancers. The mechanism of late-stage autophagy inhibitors is based on blockage of autophagolysosome formation or an increase in lysosomal pH, resulting in disrupted cargo degradation. Such inhibitors are relevant candidates for increasing anticancer therapy effectiveness. In particular, 4-aminoquoline derivatives: chloroquine/hydroxychloroquine (CQ/HCQ) have been tested in multiple clinical trials in combination with senescence-inducing anti-cancer drugs. In this review, we summarize the properties of selected late-autophagy inhibitors and their role in the regulation of autophagy and senescent cell phenotype in vitro and in vivo models of cancer as well as treatment response in clinical trials on oncological patients. Additionally, we point out that, although these compounds increase the effectiveness of treatment in some cases, their practical usage might be hindered due to systemic toxicity, hypoxic environment, dose- ant time-dependent inhibitory effects, as well as a possible contribution to escaping from TIS.
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Affiliation(s)
- Maciej Skrzeszewski
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Poland; Doctoral School of Translational Medicine, Centre of Postgraduate Medical Education, Poland
| | - Monika Maciejewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Poland
| | - Dagmara Kobza
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Poland; School of Chemistry, University of Leeds, Leeds, UK
| | - Aleksandra Gawrylak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Poland; Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Poland; Centre for Molecular Biophysics, UPR CNRS 4301, Orléans, France; Department of Molecular and Translational Oncology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Halina Waś
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Poland.
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Satou M, Wang J, Nakano-Tateno T, Teramachi M, Aoki S, Sugimoto H, Chik C, Tateno T. Autophagy inhibition suppresses hormone production and cell growth in pituitary tumor cells: A potential approach to pituitary tumors. Mol Cell Endocrinol 2024; 586:112196. [PMID: 38462123 DOI: 10.1016/j.mce.2024.112196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/12/2024]
Abstract
Pituitary tumors (PTs) represent about 10% of all intracranial tumors, and most are benign. However, some PTs exhibit continued growth despite multimodal therapies. Although temozolomide (TMZ), an alkylating chemotherapeutic agent, is a first-line medical treatment for aggressive PTs, some PTs are resistant to TMZ. Existing literature indicated the involvement of autophagy in cell growth in several types of tumors, including PTs, and autophagy inhibitors have anti-tumor effects. In this study, the expression of several autophagy-inducible genes, including Atg3, Beclin1, Map1lc3A, Map1lc3b, Ulk1, Wipi2, and Tfe3 in two PT cell lines, the mouse corticotroph AtT-20 cells and the rat mammosomatotroph GH4 cells were identified. Down regulation of Tfe3, a master switch of basal autophagy, using RNA interference, suppressed cell proliferation in AtT-20 cells, suggesting basal autophagy contributes to the maintenance of cellular functions in PT cells. Expectedly, treatment with bafilomycin A1, an autophagy inhibitor, suppressed cell proliferation, increased the cleavage of PARP1, and reduced ACTH production in AtT-20 cells. Treatment with two additional autophagy inhibitors, chloroquine (CQ) and monensin, demonstrated similar effects on cell proliferation, apoptosis, and ACTH production in AtT-20 cells. Also, treatment with CQ suppressed cell proliferation and growth hormone production in GH4 cells. Moreover, the combination of CQ and TMZ had an additive effect on the inhibition of cell proliferation in AtT-20 and GH4 cells. The additive effect of anti-cancer drugs such as CQ alone or in combination with TMZ may represent a novel therapeutic approach for PTs, in particular tumors with resistance to TMZ.
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Affiliation(s)
- Motoyasu Satou
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Jason Wang
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Tae Nakano-Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Mariko Teramachi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Shigeki Aoki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroyuki Sugimoto
- Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Constance Chik
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Toru Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
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Liu B, Yao X, Shang Y, Dai J. The multiple roles of autophagy in uveal melanoma and the microenvironment. J Cancer Res Clin Oncol 2024; 150:121. [PMID: 38467935 PMCID: PMC10927889 DOI: 10.1007/s00432-023-05576-3] [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: 09/22/2023] [Accepted: 11/09/2023] [Indexed: 03/13/2024]
Abstract
PURPOSE Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults, and effective clinical treatment strategies are still lacking. Autophagy is a lysosome-dependent degradation system that can encapsulate abnormal proteins, damaged organelles. However, dysfunctional autophagy has multiple types and plays a complex role in tumorigenicity depending on many factors, such as tumor stage, microenvironment, signaling pathway activation, and application of autophagic drugs. METHODS A systematic review of the literature was conducted to analyze the role of autophagy in UM, as well as describing the development of autophagic drugs and the link between autophagy and the tumor microenvironment. RESULTS In this review, we summarize current research advances regarding the types of autophagy, the mechanisms of autophagy, the application of autophagy inhibitors or agonists, autophagy and the tumor microenvironment. Finally, we also discuss the relationship between autophagy and UM. CONCLUSION Understanding the molecular mechanisms of how autophagy differentially affects tumor progression may help to design better therapeutic regimens to prevent and treat UM.
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Affiliation(s)
- Bo Liu
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xueting Yao
- Department of Laboratory Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Shang
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Jinhui Dai
- Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
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He K, Chen M, Liu J, Du S, Ren C, Zhang J. Nanomedicine for cancer targeted therapy with autophagy regulation. Front Immunol 2024; 14:1238827. [PMID: 38239356 PMCID: PMC10794438 DOI: 10.3389/fimmu.2023.1238827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 12/13/2023] [Indexed: 01/22/2024] Open
Abstract
Nanoparticles have unique physical and chemical properties and are currently widely used in disease diagnosis, drug delivery, and new drug development in biomedicine. In recent years, the role of nanomedical technology in cancer treatment has become increasingly obvious. Autophagy is a multi-step degradation process in cells and an important pathway for material and energy recovery. It is closely related to the occurrence and development of cancer. Because nanomaterials are highly targeted and biosafe, they can be used as carriers to deliver autophagy regulators; in addition to their favorable physicochemical properties, nanomaterials can be employed to carry autophagy inhibitors, reducing the breakdown of chemotherapy drugs by cancer cells and thereby enhancing the drug's efficacy. Furthermore, certain nanomaterials can induce autophagy, triggering oxidative stress-mediated autophagy enhancement and cell apoptosis, thus constraining the progression of cancer cells.There are various types of nanoparticles, including liposomes, micelles, polymers, metal-based materials, and carbon-based materials. The majority of clinically applicable drugs are liposomes, though other materials are currently undergoing continuous optimization. This review begins with the roles of autophagy in tumor treatment, and then focuses on the application of nanomaterials with autophagy-regulating functions in tumor treatment.
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Affiliation(s)
- Ketai He
- Department of Neurology, Joint Research Institution of Altitude Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- West China School of Stomatology, Sichuan University, Sichuan, China
| | - Mingkun Chen
- West China School of Stomatology, Sichuan University, Sichuan, China
| | - Jiao Liu
- Department of Pharmacy, Chengdu Fifth People’s Hospital, Sichuan, China
| | - Shufang Du
- West China School of Stomatology, Sichuan University, Sichuan, China
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People’s Hospital, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Lee MG, Hong HJ, Nam KS. Anthocyanin Oligomers Induce Apoptosis and Autophagy by Inhibiting the mTOR Signaling Pathway in Human Breast Cancer Cells. Pharmaceuticals (Basel) 2023; 17:24. [PMID: 38256858 PMCID: PMC10820553 DOI: 10.3390/ph17010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 01/24/2024] Open
Abstract
Anthocyanin oligomers (AOs) are phytochemicals synthesized by fermenting anthocyanins extracted from grape skins and are more biologically active than monomeric anthocyanins. In this study, we evaluate the effects of an AO on triple-negative MDA-MB-231 and HER2-overexpressing SK-BR-3 breast cancer cells. The cell viability of MDA-MB-231 and SK-BR-3 cells was significantly inhibited in a concentration-dependent manner by AO treatment for 24 h, while delphinidin (a monomeric anthocyanin) had no effect on cell viability. In addition, the AO increased H2A.X phosphorylation (a marker of DNA damage), reduced RAD51 (a DNA repair protein) and survivin (a cell survival factor) protein levels, and induced apoptosis by caspase-3-dependent PARP1 cleavage in both cell lines. Surprisingly, the AO induced autophagy by increasing intracellular LC3-II puncta and LC3-II and p62 protein levels. In addition, the AO inhibited the mTOR pathway in MDA-MB-231 and SK-BR-3 cells by suppressing the HER2, EGFR1, and AKT pathways. These results demonstrate that the anti-cancer effect of the AO was due to the induction of apoptosis and autophagy via cleaved caspase-3-mediated PARP1 cleavage and mTOR pathway inhibition, respectively. Furthermore, our results suggest that anthocyanin oligomers could be considered potential candidates for breast cancer treatment.
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Affiliation(s)
| | | | - Kyung-Soo Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea; (M.-G.L.); (H.-J.H.)
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11
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Almansa-Gómez S, Prieto-Ruiz F, Cansado J, Madrid M. Autophagy Modulation as a Potential Therapeutic Strategy in Osteosarcoma: Current Insights and Future Perspectives. Int J Mol Sci 2023; 24:13827. [PMID: 37762129 PMCID: PMC10531374 DOI: 10.3390/ijms241813827] [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: 08/07/2023] [Revised: 09/04/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Autophagy, the process that enables the recycling and degradation of cellular components, is essential for homeostasis, which occurs in response to various types of stress. Autophagy plays an important role in the genesis and evolution of osteosarcoma (OS). The conventional treatment of OS has limitations and is not always effective at controlling the disease. Therefore, numerous researchers have analyzed how controlling autophagy could be used as a treatment or strategy to reverse resistance to therapy in OS. They highlight how the inhibition of autophagy improves the efficacy of chemotherapeutic treatments and how the promotion of autophagy could prove positive in OS therapy. The modulation of autophagy can also be directed against OS stem cells, improving treatment efficacy and preventing cancer recurrence. Despite promising findings, future studies are needed to elucidate the molecular mechanisms of autophagy and its relationship to OS, as well as the mechanisms underlying the functioning of autophagic modulators. Careful evaluation is required as autophagy modulation may have adverse effects on normal cells, and the optimization of autophagic modulators for use as drugs in OS is imperative.
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Affiliation(s)
| | | | - José Cansado
- Yeast Physiology Group, Departamento de Genética y Microbiología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain; (S.A.-G.); (F.P.-R.)
| | - Marisa Madrid
- Yeast Physiology Group, Departamento de Genética y Microbiología, Facultad de Biología, Universidad de Murcia, 30100 Murcia, Spain; (S.A.-G.); (F.P.-R.)
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12
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Watson A, Lako M. Retinal organoids provide unique insights into molecular signatures of inherited retinal disease throughout retinogenesis. J Anat 2023; 243:186-203. [PMID: 36177499 PMCID: PMC10335378 DOI: 10.1111/joa.13768] [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: 06/17/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022] Open
Abstract
The demand for induced pluripotent stem cells (iPSC)-derived retinal organoid and retinal pigment epithelium (RPE) models for the modelling of inherited retinopathies has increased significantly in the last decade. These models are comparable with foetal retinas up until the later stages of retinogenesis, expressing all of the key neuronal markers necessary for retinal function. These models have proven to be invaluable in the understanding of retinogenesis, particular in the context of patient-specific diseases. Inherited retinopathies are infamously described as clinically and phenotypically heterogeneous, such that developing gene/mutation-specific animal models in each instance of retinal disease is not financially or ethically feasible. Further to this, many animal models are insufficient in the study of disease pathogenesis due to anatomical differences and failure to recapitulate human disease phenotypes. In contrast, iPSC-derived retinal models provide a high throughput platform which is physiologically relevant for studying human health and disease. They also serve as a platform for drug screening, gene therapy approaches and in vitro toxicology of novel therapeutics in pre-clinical studies. One unique characteristic of stem cell-derived retinal models is the ability to mimic in vivo retinogenesis, providing unparalleled insights into the effects of pathogenic mutations in cells of the developing retina, in a highly accessible way. This review aims to give the reader an overview of iPSC-derived retinal organoids and/or RPE in the context of disease modelling of several inherited retinopathies including Retinitis Pigmentosa, Stargardt disease and Retinoblastoma. We describe the ability of each model to recapitulate in vivo disease phenotypes, validate previous findings from animal models and identify novel pathomechanisms that underpin individual IRDs.
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Affiliation(s)
- Avril Watson
- Biosciences InstituteNewcastle UniversityNewcastle upon TyneUK
| | - Majlinda Lako
- Biosciences InstituteNewcastle UniversityNewcastle upon TyneUK
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13
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Tolue Ghasaban F, Maharati A, Akhlaghipour I, Moghbeli M. MicroRNAs as the critical regulators of autophagy-mediated cisplatin response in tumor cells. Cancer Cell Int 2023; 23:80. [PMID: 37098542 PMCID: PMC10127417 DOI: 10.1186/s12935-023-02925-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 04/12/2023] [Indexed: 04/27/2023] Open
Abstract
Chemotherapy is one of the most common therapeutic methods in advanced and metastatic tumors. Cisplatin (CDDP) is considered as one of the main first-line chemotherapy drugs in solid tumors. However, there is a high rate of CDDP resistance in cancer patients. Multi-drug resistance (MDR) as one of the main therapeutic challenges in cancer patients is associated with various cellular processes such as drug efflux, DNA repair, and autophagy. Autophagy is a cellular mechanism that protects the tumor cells toward the chemotherapeutic drugs. Therefore, autophagy regulatory factors can increase or decrease the chemotherapy response in tumor cells. MicroRNAs (miRNAs) have a pivotal role in regulation of autophagy in normal and tumor cells. Therefore, in the present review, we discussed the role of miRNAs in CDDP response through the regulation of autophagy. It has been reported that miRNAs mainly increased the CDDP sensitivity in tumor cells by inhibition of autophagy. PI3K/AKT signaling pathway and autophagy-related genes (ATGs) were the main targets of miRNAs in the regulation of autophagy-mediated CDDP response in tumor cells. This review can be an effective step to introduce the miRNAs as efficient therapeutic options to increase autophagy-mediated CDDP sensitivity in tumor cells.
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Affiliation(s)
- Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Rizvi SF, Hasan A, Parveen S, Mir SS. Untangling the complexity of heat shock protein 27 in cancer and metastasis. Arch Biochem Biophys 2023; 736:109537. [PMID: 36738981 DOI: 10.1016/j.abb.2023.109537] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/27/2022] [Accepted: 02/01/2023] [Indexed: 02/05/2023]
Abstract
Heat shock protein 27 is a type of molecular chaperone whose expression gets up-regulated due to reaction towards different stressful triggers including anticancer treatments. It is known to be a major player of resistance development in cancer cells, whereby cells are sheltered against the therapeutics that normally activate apoptosis. Heat shock protein 27 (HSP27) is one of the highly expressed proteins during various cellular insults and is a strong tumor survival factor. HSP27 influences various cellular pathways associated with cancer cell survival and growth such as apoptosis, autophagy, metastasis, angiogenesis, epithelial to mesenchymal transition, etc. HSP27 is molecular machinery which prevents the clumping of numerous substrates or client proteins which get mutated in cancer. It has been reported in several studies that targeting HSP27 is difficult because of its dynamic structure and absence of an ATP-binding site. Here, in this review, we have summarized different modulators of HSP27 and their mechanism of action as well. Effect of deregulated HSP27 in various cancer models, limitations of targeting HSP27, resistance against the conventional drugs generated due to the overexpression of HSP27, and measures to counteract this effect have also been discussed here in detail.
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Affiliation(s)
- Suroor Fatima Rizvi
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow, 226026, India.
| | - Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow, 226026, India.
| | - Sana Parveen
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow, 226026, India.
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow, 226026, India.
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15
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Wang A, Abulaiti X, Zhang H, Su H, Liu G, Gao S, Li L. Cancer Cells Evade Stress-Induced Apoptosis by Promoting HSP70-Dependent Clearance of Stress Granules. Cancers (Basel) 2022; 14:cancers14194671. [PMID: 36230594 PMCID: PMC9562925 DOI: 10.3390/cancers14194671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
The formation of stress granules (SG) is regarded as a cellular mechanism to temporarily limit protein synthesis and prevent the unfolding of proteins in stressed cells. It has been noted that SG formation can promote the survival of stressed cells. Paradoxically, however, persistent SGs could cause cell death. The underlying molecular mechanism that affects the relationship between SG dynamics and cellular states is not fully understood. Here we found that SG dynamics in cancer cells differ significantly from those in normal cells. Specifically, prolonged stress caused the formation of persistent SGs and consequently resulted in apoptosis in the normal cells. By contrast, cancer cells resolved SGs and survived the prolonged stress. Regarding the mechanism, the knockdown of HSP70 or the inhibition of the HSP70s’ ATPase activity caused defective SG clearance, leading to apoptosis in otherwise healthy cancer cells. On the other hand, the knockout of G3BPs to block the formation of SGs allowed cancer cells to escape from the HSP70 inhibition-induced apoptosis. Given the observation that SG dynamics were barely affected by the inhibition of autophagy or proteasome, we propose that SG dynamics are regulated mainly by HSP70-mediated refolding of the unfolded proteins or their removal from SGs. As a result, cancer cells evade stress-induced apoptosis by promoting the HSP70-dependent SG clearance.
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Affiliation(s)
- Aifang Wang
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xianmixinuer Abulaiti
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
- Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Han Zhang
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
| | - Hang Su
- Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People’s Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou 450053, China
| | - Guangzhi Liu
- Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People’s Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou 450053, China
| | - Shaorong Gao
- Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cells, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- Correspondence: (S.G.); (L.L.)
| | - Lingsong Li
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People’s Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou 450053, China
- Correspondence: (S.G.); (L.L.)
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16
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Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets. Int J Mol Sci 2022; 23:ijms23179734. [PMID: 36077131 PMCID: PMC9456419 DOI: 10.3390/ijms23179734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/12/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including those of the cancerous niche (i.e., hypoxia, hypermutation). Evidence suggests that excessive Bag3–HSP70 activity not only sustains, but also propagates cancers. Its role is anti-apoptotic—which allows malignant cells to persist—and intercellular—with the production of infectious ‘oncosomes’ enabling cancer expansion and recurrence. While Bag3 has been identified as a key prognostic indicator in several cancer types, its investigation is limited regarding glioblastoma. The cochaperone HSP70 has been strongly linked with GBM, while ALP inhibitors have been shown to improve GBM susceptibility to chemotherapeutics. Given the highly resilient, frequently recurrent nature of GBM, the targeting of Bag3 is a necessary consideration for the successful and definitive treatment of GBM.
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17
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Chen F, Pan Y, Xu J, Liu B, Song H. Research progress of matrine's anticancer activity and its molecular mechanism. JOURNAL OF ETHNOPHARMACOLOGY 2022; 286:114914. [PMID: 34919987 DOI: 10.1016/j.jep.2021.114914] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/02/2021] [Accepted: 12/09/2021] [Indexed: 05/12/2023]
Abstract
BACKGROUND and ethnopharmacological relevance: Matrine (MT), a type of alkaloid extracted from the Sophora family of traditional Chinese medicine, has been documented to exert a variety of pharmacological effects, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrosis, and cardiovascular protection. Sophora flavescens Aiton is a traditional Chinese medicine that is bitter and cold. Additionally, it also exhibits the effects of clearing heat, eliminating dampness, expelling insects, and promoting urination. Malignant tumors are the most important medical issue and are also the second leading cause of death worldwide. Numerous natural substances have recently been revealed to have potent anticancer properties, and several have been used in clinical trials. AIMS OF THE STUDY To summarize the antitumor effects and associated mechanisms of MT, we compiled this review by combining a huge body of relevant literature and our previous research. MATERIALS AND METHODS As demonstrated, we grouped the pharmacological effects of MT via a PubMed search. Further, we described the mechanism and current pharmacological research on MT's antitumor activity. RESULTS Additionally, extensive research has demonstrated that MT possesses superior antitumor properties, including accelerating cell apoptosis, inhibiting tumor cell growth and proliferation, inducing cell cycle arrest, inhibiting cancer metastasis and invasion, inhibiting angiogenesis, inducing autophagy, reversing multidrug resistance and inhibiting cell differentiation, thus indicating its significant potential for cancer treatment and prognosis. CONCLUSION This article summarizes current advances in research on the anticancer properties of MT and its molecular mechanism, to provide references for future research.
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Affiliation(s)
- Fengyuan Chen
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China; Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China
| | - Yunxia Pan
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Jing Xu
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Bin Liu
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
| | - Hang Song
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China; Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China.
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18
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Nath LR, Swetha M, Vijayakurup V, Thangarasu AK, Haritha NH, Shabna A, Aiswarya SU, Rayginia TP, Keerthana CK, Kalimuthu K, Sundaram S, Lankalapalli RS, Pillai S, Towner R, Isakov N, Anto RJ. Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma. Front Oncol 2022; 12:812598. [PMID: 35211405 PMCID: PMC8861526 DOI: 10.3389/fonc.2022.812598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/17/2022] [Indexed: 02/05/2023] Open
Abstract
Our previous study has demonstrated that Uttroside B (Utt-B), a saponin isolated from the leaves of Solanum nigrum Linn induces apoptosis in hepatic cancer cells and exhibits a remarkable growth inhibition of Hepatocellular Carcinoma (HCC). Our innovation has been granted a patent from the US (US 2019/0160088A1), Canada (3,026,426.), Japan (JP2019520425) and South Korea (KR1020190008323) and the technology have been transferred commercially to Q Biomed, a leading US-based Biotech company. Recently, the compound received approval as 'Orphan Drug' against HCC from US FDA, which reveals the clinical relevance of evaluating its antitumor efficacy against HCC. In the present study, we report that Utt-B promotes pro-survival autophagy in hepatic cancer cells as evidenced by the increased expression of autophagy-related proteins, including LC3-II, Beclin1, ATG 5, and ATG 7, as well as a rise in the autophagic flux. Hence, we investigated whether Utt-B-induced autophagic response is complementing or contradicting its apoptotic program in HCC. Inhibition of autophagy using the pharmacological inhibitors, Bafilomycin A1(Baf A1), and 3-methyl adenine (3-MA), and the biological inhibitor, Beclin1 siRNA, significantly enhances the apoptosis of hepatic cancer cells and hence the cytotoxicity induced by Utt-B. We also found increased expression of autophagy markers in Utt-B-treated xenografts derived from HCC. We further analyzed whether the antimalarial drug, Chloroquine (Cqn), a well-known autophagy inhibitor, can enhance the anticancer effect of Utt-B against HCC. We found that inhibition of autophagy using Cqn significantly enhances the antitumor efficacy of Utt-B in vitro and in vivo, in NOD SCID mice bearing HCC xenografts. Taken together, our results suggest that the antitumor effect of Utt-B against HCC can be further enhanced by blocking autophagy. Furthermore, Utt-B in combination with Cqn, a clinically approved drug, if repurposed and used in a combinatorial regimen with Utt-B, can further improve the therapeutic efficacy of Utt-B against HCC.
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Affiliation(s)
- Lekshmi R. Nath
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Mundanattu Swetha
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Vinod Vijayakurup
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Arun Kumar Thangarasu
- Chemical Sciences and Technology Division, Council for Scientific and Industrial Research (CSIR)-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Nair Hariprasad Haritha
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Anwar Shabna
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Sreekumar U. Aiswarya
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Department of Biotechnology, University of Calicut, Malappuram, India
| | - Tennyson P. Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - C. K. Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Kalishwaralal Kalimuthu
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Sankar Sundaram
- Department of Pathology, Government Medical College, Kottayam, India
| | - Ravi Shankar Lankalapalli
- Chemical Sciences and Technology Division, Council for Scientific and Industrial Research (CSIR)-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Sreekumar Pillai
- Department of Surgical Oncology, Jubilee Mission Medical College and Research Institute, Thrissur, India
| | - Rheal Towner
- Department of Pathology and Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma, United States
| | - Noah Isakov
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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19
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Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model. Int J Mol Sci 2021; 22:ijms222212263. [PMID: 34830158 PMCID: PMC8619060 DOI: 10.3390/ijms222212263] [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: 09/24/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 11/17/2022] Open
Abstract
Age-associated neurodegenerative diseases are known to have "impaired protein clearance" as one of the key features causing their onset and progression. Hence, homeostasis is the key to maintaining balance throughout the cellular system as an organism ages. Any imbalance in the protein clearance machinery is responsible for accumulation of unwanted proteins, leading to pathological consequences-manifesting in neurodegeneration and associated debilitating outcomes. Multiple processes are involved in regulating this phenomenon; however, failure to regulate the autophagic machinery is a critical process that hampers the protein clearing pathway, leading to neurodegeneration. Another important and widely known component that plays a role in modulating neurodegeneration is a class of proteins called sirtuins. These are class III histone deacetylases (HDACs) that are known to regulate various vital processes such as longevity, genomic stability, transcription and DNA repair. These enzymes are also known to modulate neurodegeneration in an autophagy-dependent manner. Considering its genetic relevance and ease of studying disease-related endpoints in neurodegeneration, the model system Caenorhabditis elegans has been successfully employed in deciphering various functional outcomes related to critical protein molecules, cell death pathways and their association with ageing. This review summarizes the vital role of sirtuins and autophagy in ageing and neurodegeneration, in particular highlighting the knowledge obtained using the C. elegans model system.
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20
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Han G, Zhang Y, Liu T, Li J, Li H. The anti-osteosarcoma effect from panax notoginseng saponins by inhibiting the G 0 / G 1 phase in the cell cycle and affecting p53-mediated autophagy and mitochondrial apoptosis. J Cancer 2021; 12:6383-6392. [PMID: 34659528 PMCID: PMC8489146 DOI: 10.7150/jca.54602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 03/04/2021] [Indexed: 12/26/2022] Open
Abstract
Osteosarcoma is the most common primary bone malignancy, and current chemotherapy sessions against it often induce severe complications in patients. Thus, it is necessary to develop new and effective antineoplastic agents with fewer side effects. Panax notoginseng saponins (PNS) are the active components in panax notoginseng and were reported to be capable of inhibiting the growth of several tumors both in vitro and in vivo. However, its effects on osteosarcoma have not been studied yet, which is addressed in this study for the first time. Our results indicated that PNS can inhibit proliferation, invasion and migration of the osteosarcoma cells, while promoting their apoptosis simultaneously. Specifically, PNS caused an increase in mitochondrial membrane potential and the amount of reactive oxygen species. The cell cycle in osteosarcoma cells was arrested in the G0 / G1 phase after PNS treatment. The expression of p53 and other apoptosis-related mitochondrial proteins were promoted. Nevertheless, it was observed that autophagy became less active in osteosarcoma cells when PNS was administered. In a word, PNS were of potential therapeutic significance for osteosarcoma.
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Affiliation(s)
- Guangtao Han
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yubiao Zhang
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ting Liu
- Department of Orthopedics, Hospital of Shenmu, Shenmu, Shaanxi, 719300, P.R. China
| | - Jianping Li
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Haohuan Li
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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21
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Cerda-Troncoso C, Varas-Godoy M, Burgos PV. Pro-Tumoral Functions of Autophagy Receptors in the Modulation of Cancer Progression. Front Oncol 2021; 10:619727. [PMID: 33634029 PMCID: PMC7902017 DOI: 10.3389/fonc.2020.619727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/10/2020] [Indexed: 12/20/2022] Open
Abstract
Cancer progression involves a variety of pro-tumorigenic biological processes including cell proliferation, migration, invasion, and survival. A cellular pathway implicated in these pro-tumorigenic processes is autophagy, a catabolic route used for recycling of cytoplasmic components to generate macromolecular building blocks and energy, under stress conditions, to remove damaged cellular constituents to adapt to changing nutrient conditions and to maintain cellular homeostasis. During autophagy, cells form a double-membrane sequestering a compartment termed the phagophore, which matures into an autophagosome. Following fusion with the lysosome, the cargo is degraded inside the autolysosomes and the resulting macromolecules released back into the cytosol for reuse. Cancer cells use this recycling system during cancer progression, however the key autophagy players involved in this disease is unclear. Accumulative evidences show that autophagy receptors, crucial players for selective autophagy, are overexpressed during cancer progression, yet the mechanisms whereby pro-tumorigenic biological processes are modulated by these receptors remains unknown. In this review, we summarized the most important findings related with the pro-tumorigenic role of autophagy receptors p62/SQSTM1, NBR1, NDP52, and OPTN in cancer progression. In addition, we showed the most relevant cargos degraded by these receptors that have been shown to function as critical regulators of pro-tumorigenic processes. Finally, we discussed the role of autophagy receptors in the context of the cellular pathways implicated in this disease, such as growth factors signaling, oxidative stress response and apoptosis. In summary, we highlight that autophagy receptors should be considered important players of cancer progression, which could offer a niche for the development of novel diagnosis and cancer treatment strategies.
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Affiliation(s)
- Cristóbal Cerda-Troncoso
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Manuel Varas-Godoy
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Patricia V. Burgos
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Hui B, Hou X, Liu R, Liu XH, Hu Z. Gypenoside inhibits ox-LDL uptake and foam cell formation through enhancing Sirt1-FOXO1 mediated autophagy flux restoration. Life Sci 2020; 264:118721. [PMID: 33160993 DOI: 10.1016/j.lfs.2020.118721] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 10/26/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gypenoside (GP) is the major bioactive constituent of G. pentaphyllum, a traditional Chinese medicine. It has been reported that GP can affect autophagy and lipid metabolism in cultured cells. We hypothesize that GP can inhibit foam cell formation in cultured macrophages through autophagy modulation. METHODS THP1 cells were cultured and treated with oxidized low-density lipoprotein (ox-LDL), followed by GP treatment at different concentrations. The autophagy flux was evaluated using western blot and confocal microscope analyses. The ox-LDL uptake and foam cell formation abilities were measured. RESULTS We found that ox-LDL impaired the autophagy flux in the cultured macrophages, indicated by a significant reduction of LC3-II and autophagosome puncta quantification, as well as an accumulation of p62 proteins. GP treatment, however, dose-dependently restored the autophagy flux impaired by ox-LDL and reduced the ox-LDL uptake and foam cell transformation from THP1 cells, which can be alleviated, or exacerbated, by modulation of autophagy status using autophagy enhancer or inhibitor. Coimmunoprecipitation assays showed that GP up-regulated Srit1 and FOXO1 expression and enhanced their direct interaction, and thus contributed to the regulation of autophagy. CONCLUSION GP inhibits ox-LDL uptake and foam cell formation through enhancing Sirt1-FOXO1 mediated autophagy flux restoration, suggesting this compound has therapeutic potential for atherosclerosis.
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Affiliation(s)
- Bo Hui
- Department of Cardiology, Qingdao Municipal Hospital of Qingdao University, Qingdao, 266071, China
| | - Xuwei Hou
- School of Medicine, the University of Missouri, Columbia, MO 65201, USA
| | - Ruhui Liu
- Department of Cardiovascular Diseases, Tongji Hospital of Tongji University, Shanghai 200065, China
| | - Xiao-Hong Liu
- Cardiovascular Department of Internal Medicine, Central Hospital of Karamay, Karamay 834000, Xinjiang Uyghur Autonomous Region, China.
| | - Zhaohui Hu
- Department of Cardiovascular Diseases, Tongji Hospital of Tongji University, Shanghai 200065, China.
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Du J, Li J, Song D, Li Q, Li L, Li B, Li L. Matrine exerts anti‑breast cancer activity by mediating apoptosis and protective autophagy via the AKT/mTOR pathway in MCF‑7 cells. Mol Med Rep 2020; 22:3659-3666. [PMID: 33000249 PMCID: PMC7533454 DOI: 10.3892/mmr.2020.11449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 06/11/2020] [Indexed: 12/29/2022] Open
Abstract
Matrine, a major alkaloid isolated from the traditional Chinese herb Sophora flavescens, has been used clinically to treat breast cancer in China. However, the effects of matrine on apoptosis and autophagy in breast cancer cells remain unclear. In the present study, the anti‑breast cancer capacity of matrine was evaluated and its role in regulating apoptosis and autophagy in vitro was investigated. Matrine significantly inhibited the growth of MCF‑7 cells. In addition, Hoechst 33342 staining and Annexin V/propidium iodide staining demonstrated that incubation with matrine induced apoptosis in MCF‑7 cells. Furthermore, matrine induced autophagy in MCF‑7 cells, manifesting as an accumulation of light chain 3 II and downregulation of p62. Additionally, matrine suppressed AKT and mammalian target of rapamycin (mTOR) phosphorylation, indicating that the AKT/mTOR pathway is involved in matrine‑induced apoptosis and autophagy. Overall, the results of the present study indicated that matrine possesses anti‑breast cancer activity by providing protective autophagy via inhibition of the AKT/mTOR pathway. These findings indicated that matrine may be a promising candidate for drug development targeting breast cancer.
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Affiliation(s)
- Jikun Du
- Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
- Central Research Laboratory, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, The Second People's Hospital of Bao'an Shenzhen (Group), Shajing People's Hospital of Bao'an Shenzhen, Shenzhen, Guangdong 518104, P.R. China
| | - Jinwen Li
- Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Daibo Song
- Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Qin Li
- Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Lin Li
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Baohong Li
- Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Li Li
- Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12040919. [PMID: 32283634 PMCID: PMC7225937 DOI: 10.3390/cancers12040919] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 01/01/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate—a drug used to treat malaria—has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.
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Khan T, Relitti N, Brindisi M, Magnano S, Zisterer D, Gemma S, Butini S, Campiani G. Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas. Med Res Rev 2019; 40:1002-1060. [PMID: 31742748 DOI: 10.1002/med.21646] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/16/2019] [Accepted: 11/08/2019] [Indexed: 02/06/2023]
Abstract
Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC. Additionally, we provide a viewpoint on the state of the art and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC.
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Affiliation(s)
- Tuhina Khan
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Nicola Relitti
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Margherita Brindisi
- Department of Pharmacy, Department of Excellence 2018-2022, University of Napoli Federico IL, Napoli, Italy
| | - Stefania Magnano
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin, Dublin 2, Ireland
| | - Daniela Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin, Dublin 2, Ireland
| | - Sandra Gemma
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Stefania Butini
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
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Bouhamdani N, Comeau D, Cormier K, Turcotte S. STF-62247 accumulates in lysosomes and blocks late stages of autophagy to selectively target von Hippel-Lindau-inactivated cells. Am J Physiol Cell Physiol 2019; 316:C605-C620. [DOI: 10.1152/ajpcell.00483.2018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Autophagy is a highly conserved, homeostatic process by which cytosolic components reach lysosomes for degradation. The roles played by different autophagic processes in cancer are complex and remain cancer type and stage dependent. Renal cell carcinoma (RCC) is the most common subtype of kidney cancer and is characterized by the inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Our previous study identified a small compound, STF-62247, as an autophagy-modulating molecule causing selective cytotoxicity for VHL-inactivated cells. This present study investigates the effects of STF-62247 specifically on the macroautophagic flux to better characterize its mechanism of action in RCC. Our results clearly demonstrate that this compound is a potent blocker of late stages of autophagy. We show that inhibiting autophagy by CRISPR knockouts of autophagy-related genes rendered VHL-deficient cells insensitive to STF-62247, uncovering the importance of the autophagic pathway in STF-selective cell death. By exploiting the autofluorescence of STF-62247, we pinpointed its cellular localization to lysosomes. Finally, in response to prolonged STF treatments, we show that VHL-proficient cells are able to surmount the block in late stages of autophagy by restoring their lysosome numbers. Conversely, an increase in autophagic vesicles accompanied by a time-dependent decrease in lysosomes was observed in VHL-deficient cells. This is the first mechanistic study investigating STF-62447’s effects on the autophagic flux in RCC. Importantly, our study reclassifies STF-62247 as a blocker of later stages of autophagy and highlights the possibility of blocking this process through lysosome disruption in VHL-mutated RCCs.
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Affiliation(s)
- Nadia Bouhamdani
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
| | - Dominique Comeau
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
| | - Kevin Cormier
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
| | - Sandra Turcotte
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
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Autophagy as a molecular target for cancer treatment. Eur J Pharm Sci 2019; 134:116-137. [PMID: 30981885 DOI: 10.1016/j.ejps.2019.04.011] [Citation(s) in RCA: 254] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 04/04/2019] [Accepted: 04/05/2019] [Indexed: 12/22/2022]
Abstract
Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.
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28
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Angelova DM, Brown DR. Altered Processing of β-Amyloid in SH-SY5Y Cells Induced by Model Senescent Microglia. ACS Chem Neurosci 2018; 9:3137-3152. [PMID: 30052418 DOI: 10.1021/acschemneuro.8b00334] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The single greatest risk factor for neurodegenerative diseases is aging. Aging of cells such as microglia in the nervous system has an impact not only on the ability of those cells to function but also on cells they interact with. We have developed a model microglia system that recapitulates the dystrophic/senescent phenotype, and we have combined this with the study of β-amyloid processing. The model is based on the observation that aged microglia have increased iron content. By overloading a human microglial cell line with iron, we were able to change the secretory profile of the microglia. When combining these senescent microglia with SH-SY5Y cells, we noted an increase in extracellular β-amyloid. The increased levels of β-amyloid were due to a decrease in the release of insulin-degrading enzyme by the model senescent microglia. Further analysis revealed that the senescent microglia showed both decreased autophagy and increased ER stress. These studies demonstrate the potential impact of an aging microglial population in terms of β-amyloid produced by neurons, which could play a causal role in diseases like Alzheimer's disease. Our results also further develop the potential utility of an in vitro model of senescent microglia for the study of brain aging and neurodegenerative disease.
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Affiliation(s)
- Dafina M. Angelova
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, U.K
| | - David R. Brown
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, U.K
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29
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Wang M, Law ME, Castellano RK, Law BK. The unfolded protein response as a target for anticancer therapeutics. Crit Rev Oncol Hematol 2018; 127:66-79. [DOI: 10.1016/j.critrevonc.2018.05.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 01/22/2018] [Accepted: 05/07/2018] [Indexed: 12/11/2022] Open
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30
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Livingston JA, Wang WL, Tsai JW, Lazar AJ, Leung CH, Lin H, Advani S, Daw N, Santiago-O'Farrill J, Hollomon M, Gordon NB, Kleinerman ES. Analysis of HSP27 and the Autophagy Marker LC3B + Puncta Following Preoperative Chemotherapy Identifies High-Risk Osteosarcoma Patients. Mol Cancer Ther 2018; 17:1315-1323. [PMID: 29592877 PMCID: PMC5984702 DOI: 10.1158/1535-7163.mct-17-0901] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 01/11/2018] [Accepted: 03/20/2018] [Indexed: 12/30/2022]
Abstract
Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; P = 0.023 and <0.001). Among 215 patients with localized osteosarcoma, both pre-treatment [multivariate hazard ratio (HR), 26.7; 95% confidence interval (CI), 1.47-484; P = 0.026] and post-treatment HSP27 expression (multivariate HR, 1.85; 95% CI, 1.03-3.33; P = 0.039) were associated with worse OS. Lack of LC3B+ puncta at resection was an independent poor prognostic marker in both univariate (HR, 1.78; 95% CI, 1.05-3.03; P = 0.034) and multivariate models (HR, 1.75; 95% CI, 1.01-3.04; P = 0.045). Patients with LC3B+/HSP27- tumors at resection had the best 10-year OS (75%) whereas patients with LC3B-/HSP27+ tumors had the worst 10-year survival (25%). Neither HSP27 expression nor the presence of LCB3+ puncta was correlated with pathologic treatment response. Our findings establish HSP27 expression and LC3B+ puncta as independent prognostic markers in osteosarcoma patients receiving standard chemotherapy and support further investigation into strategies targeting HSP27 or modulating autophagy in osteosarcoma treatment. Mol Cancer Ther; 17(6); 1315-23. ©2018 AACR.
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Affiliation(s)
- J Andrew Livingston
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei-Lien Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jen-Wei Tsai
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexander J Lazar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cheuk Hong Leung
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Heather Lin
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shailesh Advani
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Najat Daw
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Mario Hollomon
- Department of Biology, Texas Southern University, Houston, Texas
| | - Nancy B Gordon
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eugenie S Kleinerman
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Ma H, Li X, Wang J, Hornicek F, Garbutt C, Chang X, Duan Z. Expression and Clinical Implication of Autophagy-Associated Protein p62 in Osteosarcoma. Oncology 2018; 95:52-60. [DOI: 10.1159/000487437] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 01/25/2018] [Indexed: 12/31/2022]
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mTOR: An attractive therapeutic target for osteosarcoma? Oncotarget 2018; 7:50805-50813. [PMID: 27177330 PMCID: PMC5226621 DOI: 10.18632/oncotarget.9305] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 05/05/2016] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma (OS) is a common primary malignant bone tumor with high morbidity and mortality in children and young adults. How to improve poor prognosis of OS due to resistance to chemotherapy remains a challenge. Recently, growing findings show activation of mammalian target of rapamycin (mTOR), is associated with OS cell growth, proliferation, metastasis. Targeting mTOR may be a promising therapeutic approach for treating OS. This review summarizes the roles of mTOR pathway in OS and present research status of mTOR inhibitors in the context of OS. In addition, we have attempted to discuss how to design a better treatment project for OS by combining mTOR inhibitor with other drugs.
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Chen N, Han Y, Luo Y, Zhou Y, Hu X, Yu Y, Xie X, Yin M, Sun J, Zhong W, Zhao Y, Song H, Fan C. Nanodiamond-based non-canonical autophagy inhibitor synergistically induces cell death in oxygen-deprived tumors. MATERIALS HORIZONS 2018; 5:1204-1210. [DOI: 10.1039/c8mh00993g] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
Abstract
Blockage of autophagic flux by nanodiamonds induces apoptosis in hypoxic tumor cells with minimal toxicity to normal tissues and enhances the effects of anti-angiogenic therapy.
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Zou N, Wei Y, Li F, Yang Y, Cheng X, Wang C. The inhibitory effects of compound Muniziqi granule against B16 cells and harmine induced autophagy and apoptosis by inhibiting Akt/mTOR pathway. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:517. [PMID: 29197358 PMCID: PMC5712103 DOI: 10.1186/s12906-017-2017-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 11/19/2017] [Indexed: 12/27/2022]
Abstract
Background Compound Muniziqi granule (MNZQ) is a multi-component herbal preparation and a popular traditional Uighur medicine used in China for treating endocrine disorder-induced acne, chloasma, dysmenorrhea, menopausal syndrome, and melanoma. Harmine presented in MNZQ has been confirmed potential anticancer effect on the B16 cells among others. The purpose of this study is to explore the inhibitory effects of MNZQ against B16 cells and mechanism of autophagy and apoptosis induced by harmine in B16 cells. Methods The cell viability was calculated by CCK8 assay. The in vitro tyrosinase activity was determined by spectrophotometry. The harmine-induced autophagy was demonstrated by electron microscopy and MDC staining. Flow cytometry was used to measure cell death and cell cycle distribution. All proteins expression was assessed by western blot. Results MNZQ and some herb extracts contained in preparation displayed inhibitory effects on B16 cells but without inhibition on mushroom tyrosinase compared with kojic acid. The formation of autophagosome was markedly induced by harmine with the accretion of LC3-II and the degeneration of p62 in B16 cells, which indicated that harmine was an autophagy inducer. Cell death and sub-G2 population suggested that harmine could induce cell death. Particularly, 3-MA, an autophagy inhibitor, was discovered to prevent harmine-induced decrease of the cell viability and cell cycle arrest on G2 phase, indicating that autophagy was vital to the cell death. In addition, the results indicated that harmine could inhibit the phosphorylation of Akt and mTOR, which might mediate autophagy. Conclusion Harmine could induce autophagy and apoptosis by inhibiting Akt/mTOR pathway in B16 cells. Harmine might be a promising therapeutic agent for treatment of melanoma in MNZQ.
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Hwang HY, Cho SM, Kwon HJ. Approaches for discovering novel bioactive small molecules targeting autophagy. Expert Opin Drug Discov 2017; 12:909-923. [PMID: 28758515 DOI: 10.1080/17460441.2017.1349751] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION In recent years, development of novel bioactive small molecules targeting autophagy has been implicated for autophagy-related disease treatment. Screening new small molecules regulating autophagy allows for the discovery of novel autophagy machinery and therapeutic agents. Areas covered: Two major screening methods for novel autophagy modulators are introduced in this review, namely target based screening and phenotype based screening. With increasing attention focused on chemical compound libraries, coupled with the development of new assay systems, this review attempts to provide an efficient strategy to explore autophagy biology and discover small molecules for the treatment of autophagy-related diseases. Expert opinion: Adopting an appropriate autophagy screening strategy is important for developing small molecules capable of treating neurodegenerative diseases and cancers. Phenotype based screening and target based screening were both used for developing effective small molecules. However, each of these methods has many pros and cons. An efficient approach is suggested to screen for novel lead compounds targeting autophagy, which could provide new hits with better efficiency and rapidity.
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Affiliation(s)
- Hui-Yun Hwang
- a Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology , Yonsei University , Seoul , Republic of Korea
| | - Sung Min Cho
- a Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology , Yonsei University , Seoul , Republic of Korea
| | - Ho Jeong Kwon
- a Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology , Yonsei University , Seoul , Republic of Korea
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Autophagy as a potential target for sarcoma treatment. Biochim Biophys Acta Rev Cancer 2017; 1868:40-50. [PMID: 28242349 DOI: 10.1016/j.bbcan.2017.02.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 02/23/2017] [Accepted: 02/23/2017] [Indexed: 02/05/2023]
Abstract
Autophagy is a constitutively active, evolutionary conserved, catabolic process for maintaining homeostasis in cellular stress responses and cell survival. Although its mechanism has not been fully illustrated, recent work on autophagy in various types of sarcomas has demonstrated that autophagy exerts an important role in sarcoma cell growth and proliferation, in pro-survival response to therapies and stresses, and in therapeutic resistance of sarcoma. Thus, the autophagic process is being seen as a possibly novel therapeutic target of sarcoma. Additionally, some co-regulators of autophagy have also been investigated as promising biomarkers for the diagnosis and prognosis of sarcoma. In this review, we summarize contemporary advances in the role of autophagy in sarcoma and discuss the potential of autophagy as a new target for sarcoma treatment.
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Chen R, Li X, He B, Hu W. MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma. Mol Med Rep 2017; 15:1326-1334. [PMID: 28138700 PMCID: PMC5367354 DOI: 10.3892/mmr.2017.6149] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 06/09/2016] [Indexed: 01/28/2023] Open
Abstract
Osteosarcoma, which is the most common type of primary bone tumor in adolescents, is characterized by complex genetic alterations and frequent resistance to conventional treatments. MicroRNAs (miRs) have emerged as fundamental regulators in gene expression through their ability to silence gene expression at post-transcriptional and translational levels. The present study investigated the role of miR-410 in the progression of osteosarcoma. The results demonstrated that the expression of miR-410 was markedly downregulated in human osteosarcoma tissues, and U2OS and MG-63 osteosarcoma cell lines. Clinicopathological significance suggested that miR-410 may be a potential biomarker for chemotherapy-resistant osteosarcoma. Furthermore, overexpression of miR-410 exhibited a limited effect on cell viability in U2OS and MG-63 cells. Target prediction algorithms (TargetScan and miRanda) indicated that autophagy related 16-like 1 (ATG16L1) was a potential target gene of miR-410. A luciferase reporter assay demonstrated that miR-410 directly decreased ATG16L1 expression by targeting its 3′-untranslated region. In addition, the results revealed that miR-410 was able to markedly inhibit autophagy. Accordingly, autophagy was activated as a protective mechanism when osteosarcoma cells were exposed to three common anticancer drugs, including rapamycin, doxorubicin and cisplatin. Furthermore, the autophagy inhibitor 3-methyladenine and miR-410 expression were able to improve the therapeutic response of the cells to chemotherapy drugs (rapamycin, doxorubicin and cisplatin), thus indicating that miR-410 enhanced chemosensitivity through autophagy inhibition in osteosarcoma cells. In conclusion, studies regarding the function of miR-410 on autophagy provided insight into the biological function of miR-410 in osteosarcoma and may offer a promising approach for the treatment of osteosarcoma.
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Affiliation(s)
- Ren Chen
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiaohai Li
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Bin He
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Hu
- Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Maroni P, Bendinelli P, Resnati M, Matteucci E, Milan E, Desiderio MA. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages. Int J Mol Sci 2016; 17:443. [PMID: 27023526 PMCID: PMC4848899 DOI: 10.3390/ijms17040443] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 03/09/2016] [Accepted: 03/09/2016] [Indexed: 12/14/2022] Open
Abstract
Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination.
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Affiliation(s)
- Paola Maroni
- Istituto Ortopedico Galeazzi, Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Milano 20161, Italy.
| | - Paola Bendinelli
- Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano 20133, Italy.
| | - Massimo Resnati
- San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milano 20133, Italy.
| | - Emanuela Matteucci
- Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano 20133, Italy.
| | - Enrico Milan
- San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milano 20133, Italy.
| | - Maria Alfonsina Desiderio
- Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano 20133, Italy.
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Lu Y, Zhang R, Liu S, Zhao Y, Gao J, Zhu L. ZT-25, a new vacuolar H(+)-ATPase inhibitor, induces apoptosis and protective autophagy through ROS generation in HepG2 cells. Eur J Pharmacol 2015; 771:130-8. [PMID: 26689625 DOI: 10.1016/j.ejphar.2015.12.026] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 12/06/2015] [Accepted: 12/11/2015] [Indexed: 12/29/2022]
Abstract
The vacuolar H(+)-ATPase (V-ATPase) has recently been proposed as a key target for new strategies in cancer treatment. Our previous work has proved that diphyllin glycoside is a novel inhibitor of V-ATPase. Here the cytotoxic effects of ZT-25, the most potent diphyllin glycoside derivatives, were studied and some of the underlying mechanisms were elucidated. ZT-25 displayed strong cytotoxicity on several cancer cell lines and relatively low cytotoxicity on human fetal hepatic cells (WRL-68) at submicromolar concentrations. In human hepatoma cells HepG2, ZT-25 induced G1/G0 phase arrest and apoptosis, as well as mitochondrial membrane potential (MMP) dissipation and ATP depletion. Furthermore, Bcl-2 protein decreased, while Bax protein and cleaved caspase-3 protein increased upon ZT-25 treatment. Benzyloxycarbony (Cbz)-l-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK), a well-known pan-caspase inhibitor, attenuated ZT-25-induced cell death, suggesting the involvement of caspase-dependent pathway. Intriguingly, ZT-25 induced autophagy in HepG2 cells as characterized by increased the conversion of LC3 I to LC3 II, Beclin-1 expression and autophagosome formation. Meanwhile, p-mTOR expression was decreased which indicated that ZT-25-induced autophagy might be mediated through the suppression of mTOR pathway. Inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) obviously promoted ZT-25-induced cell death, suggesting the protective role of autophagy. Increased intracellular ROS level was found to be the early event in ZT-25-treated HepG2 cells. Inhibition of ROS generation by N-acetyl-l-cysteine (NAC) attenuated ZT-25-induced cell death and autophagy. Together, these results provide key insights into the ZT-25-induced cytotoxicity in HepG2 cells, which will have a great impact on the further development of diphyllin derivatives.
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Affiliation(s)
- Yapeng Lu
- School of Medicine, Jiangsu University, Zhenjiang 212013, China; Institute of Nautical Medicine, Nantong University, Nantong 226019, China
| | - Rui Zhang
- Department of Neurology, Deji Hospital, Shanghai 200331, China
| | - Siyuan Liu
- Institute of Nautical Medicine, Nantong University, Nantong 226019, China
| | - Yu Zhao
- Institute of Nautical Medicine, Nantong University, Nantong 226019, China
| | - Jing Gao
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.
| | - Li Zhu
- Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
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Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 2015; 35 Suppl:S25-S54. [PMID: 25892662 PMCID: PMC4898971 DOI: 10.1016/j.semcancer.2015.02.006] [Citation(s) in RCA: 464] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 02/08/2023]
Abstract
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, Temple University, Philadelphia, PA, United States.
| | - Alla Arzumanyan
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Rob J Kulathinal
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Stacy W Blain
- Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
| | - Randall F Holcombe
- Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, United States
| | - Jamal Mahajna
- MIGAL-Galilee Technology Center, Cancer Drug Discovery Program, Kiryat Shmona, Israel
| | - Maria Marino
- Department of Science, University Roma Tre, V.le G. Marconi, 446, 00146 Rome, Italy
| | - Maria L Martinez-Chantar
- Metabolomic Unit, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain
| | - Roman Nawroth
- Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Isidro Sanchez-Garcia
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Dipali Sharma
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Neeraj K Saxena
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
| | - Neetu Singh
- Tissue and Cell Culture Unit, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India
| | | | - Shanchun Guo
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - S Salman Ashraf
- Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - Chandra S Boosani
- Department of BioMedical Sciences, Creighton University, Omaha, NE, United States
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Sophie Chen
- Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey GU2 7YG, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Asfar S Azmi
- Department of Pathology, Karmonas Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States
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41
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Hassan M, Selimovic D, Hannig M, Haikel Y, Brodell RT, Megahed M. Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment. World J Exp Med 2015; 5:206-217. [PMID: 26618107 PMCID: PMC4655250 DOI: 10.5493/wjem.v5.i4.206] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 06/29/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanoma's extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment.
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42
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Li Y, Zhu H, Wang S, Qian X, Fan J, Wang Z, Song P, Zhang X, Lu W, Ju D. Interplay of Oxidative Stress and Autophagy in PAMAM Dendrimers-Induced Neuronal Cell Death. Am J Cancer Res 2015; 5:1363-77. [PMID: 26516373 PMCID: PMC4615738 DOI: 10.7150/thno.13181] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 08/30/2015] [Indexed: 01/07/2023] Open
Abstract
Poly-amidoamine (PAMAM) dendrimers are proposed to be one of the most promising drug-delivery nanomaterials. However, the toxicity of PAMAM dendrimers on the central nervous system seriously hinders their medical applications. The relationship between oxidative stress and autophagy induced by PAMAM dendrimers, and its underlying mechanism remain confusing. In this study, we reported that PAMAM dendrimers induced both reactive oxygen species and autophagy flux in neuronal cells. Interestingly, autophagy might be triggered by the formation of reactive oxygen species induced by PAMAM dendrimers. Suppression of reactive oxygen species could not only impair PAMAM dendrimers-induced autophagic effects, but also reduce PAMAM dendrimers-induced neuronal cell death. Moreover, inhibition of autophagy could protect against PAMAM dendrimers-induced neuronal cell death. These findings systematically elucidated the interplay between oxidative stress and autophagy in the neurotoxicity of PAMAM dendrimers, which might encourage the application of antioxidants and autophagy inhibitors to ameliorate the neurotoxicity of PAMAM dendrimers in clinic.
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Nyasae LK, Schell MJ, Hubbard AL. Copper directs ATP7B to the apical domain of hepatic cells via basolateral endosomes. Traffic 2014; 15:1344-65. [PMID: 25243755 DOI: 10.1111/tra.12229] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 09/16/2014] [Indexed: 01/01/2023]
Abstract
Physiologic Cu levels regulate the intracellular location of the Cu ATPase ATP7B. Here, we determined the routes of Cu-directed trafficking of endogenous ATP7B in the polarized hepatic cell line WIF-B and in the liver in vivo. Copper (10 µm) caused ATP7B to exit the trans-Golgi network (TGN) in vesicles, which trafficked via large basolateral endosomes to the apical domain within 1 h. Although perturbants of luminal acidification had little effect on the TGN localization of ATP7B in low Cu, they blocked delivery to the apical membrane in elevated Cu. If the vesicular proton-pump inhibitor bafilomycin-A1 (Baf) was present with Cu, ATP7B still exited the TGN, but accumulated in large endosomes located near the coverslip, in the basolateral region. Baf washout restored ATP7B trafficking to the apical domain. If ATP7B was staged apically in high Cu, Baf addition promoted the accumulation of ATP7B in subapical endosomes, indicating a blockade of apical recycling, with concomitant loss of ATP7B at the apical membrane. The retrograde pathway to the TGN, induced by Cu removal, was far less affected by Baf than the anterograde (Cu-stimulated) case. Overall, loss of acidification-impaired Cu-regulated trafficking of ATP7B at two main sites: (i) sorting and exit from large basolateral endosomes and (ii) recycling via endosomes near the apical membrane.
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Affiliation(s)
- Lydia K Nyasae
- Department of Cell Biology, The Johns Hopkins School of Medicine, 725 N. Wolfe Street, Baltimore, MD, 20184, USA
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