Autophagy and intermittent fasting: the connection for cancer therapy?

Cancer is a leading cause of death worldwide, and its incidence is continually increasing. Although anticancer therapy has improved significantly, it still has limited efficacy for tumor eradication and is highly toxic to healthy cells. Thus, novel therapeutic strategies to improve chemotherapy, radiotherapy and targeted therapy are an important goal in cancer research. Macroautophagy (herein referred to as autophagy) is a conserved lysosomal degradation pathway for the intracellular recycling of macromolecules and clearance of damaged organelles and misfolded proteins to ensure cellular homeostasis. Dysfunctional autophagy contributes to many diseases, including cancer. Autophagy can suppress or promote tumors depending on the developmental stage and tumor type, and modulating autophagy for cancer treatment is an interesting therapeutic approach currently under intense investigation. Nutritional restriction is a promising protocol to modulate autophagy and enhance the efficacy of anticancer therapies while protecting normal cells. Here, the description and role of autophagy in tumorigenesis will be summarized. Moreover, the possibility of using fasting as an adjuvant therapy for cancer treatment, as well as the molecular mechanisms underlying this approach, will be presented.

[1]  E. White Deconvoluting the context-dependent role for autophagy in cancer , 2012, Nature Reviews Cancer.

[2]  G. Fimia,et al.  Emerging Mechanisms in Initiating and Terminating Autophagy. , 2017, Trends in biochemical sciences.

[3]  N. Chen,et al.  Autophagy as a therapeutic target in cancer , 2011, Cancer biology & therapy.

[4]  N. Simone,et al.  Selectively starving cancer cells through dietary manipulation: methods and clinical implications. , 2013, Future oncology.

[5]  A. Ballestrero,et al.  Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition , 2015, Oncotarget.

[6]  M. Mattson,et al.  Impact of intermittent fasting on health and disease processes , 2017, Ageing Research Reviews.

[7]  Congcong He,et al.  The Beclin 1 interactome. , 2010, Current opinion in cell biology.

[8]  Junying Yuan,et al.  Pharmacologic agents targeting autophagy. , 2015, The Journal of clinical investigation.

[9]  Chang S. Chan,et al.  Mutational Landscape of the Essential Autophagy Gene BECN1 in Human Cancers , 2014, Molecular Cancer Research.

[10]  Yukai He,et al.  Curcumin inhibits cell proliferation and promotes apoptosis of laryngeal cancer cells through Bcl-2 and PI3K/Akt, and by upregulating miR-15a. , 2017, Oncology letters.

[11]  M. Vinciguerra,et al.  Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models , 2015, Oncotarget.

[12]  Lorenzo Galluzzi,et al.  Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles , 2017, Nature Reviews Drug Discovery.

[13]  R. Amaravadi,et al.  Targeting autophagy in cancer , 2018, Cancer.

[14]  K. Cadwell Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis , 2016, Nature Reviews Immunology.

[15]  Mark P Mattson,et al.  Fasting: molecular mechanisms and clinical applications. , 2014, Cell metabolism.

[16]  Mary G. Lin,et al.  Structure and function of the ULK1 complex in autophagy. , 2016, Current opinion in cell biology.

[17]  D. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[18]  M. Vinciguerra,et al.  Fasting inhibits hepatic stellate cells activation and potentiates anti‐cancer activity of Sorafenib in hepatocellular cancer cells , 2018, Journal of cellular physiology.

[19]  V. Jain,et al.  Targeting glucose metabolism with 2-deoxy-D-glucose for improving cancer therapy. , 2009, Future oncology.

[20]  Steven J. M. Jones,et al.  Cross-cancer profiling of molecular alterations within the human autophagy interaction network , 2015, Autophagy.

[21]  T. Dorff,et al.  Fasting and cancer treatment in humans: A case series report , 2009, Aging.

[22]  J. McCubrey,et al.  Current treatment strategies for inhibiting mTOR in cancer. , 2015, Trends in pharmacological sciences.

[23]  S. Fulda Autophagy in Cancer Therapy , 2017, Front. Oncol..

[24]  M. Zamora,et al.  Autophagy Promotes Focal Adhesion Disassembly and Cell Motility of Metastatic Tumor Cells through the Direct Interaction of Paxillin with LC3. , 2016, Cell reports.

[25]  C. Kenific,et al.  Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation , 2011, Molecular biology of the cell.

[26]  Robin Mathew,et al.  Role of autophagy in cancer , 2007, Nature Reviews Cancer.

[27]  S. Ravera,et al.  Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models , 2015, Oncotarget.

[28]  Takeshi Noda,et al.  A ubiquitin-like system mediates protein lipidation , 2000, Nature.

[29]  Caloric restriction. , 1998, Aging.

[30]  A. Ballabio,et al.  Molecular definitions of autophagy and related processes , 2017, The EMBO journal.

[31]  R. Riechelmann,et al.  Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer. , 2016, Clinical colorectal cancer.

[32]  C. Kenific,et al.  Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. , 2014, Cancer discovery.

[33]  Vito Pistoia,et al.  Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy , 2012, Science Translational Medicine.

[34]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[35]  H. Putter,et al.  The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study , 2015, BMC Cancer.

[36]  A. Ballabio,et al.  TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop , 2013, Nature Cell Biology.

[37]  L. Galluzzi,et al.  Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy , 2017, Nature Reviews Clinical Oncology.

[38]  Y. Ohsumi,et al.  Isolation and characterization of autophagy‐defective mutants of Saccharomyces cerevisiae , 1993, FEBS letters.

[39]  Kevin Bray,et al.  Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. , 2006, Cancer cell.

[40]  T. Dorff,et al.  Fasting and differential chemotherapy protection in patients , 2010, Cell cycle.

[41]  H. Coller,et al.  Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. , 2011, Genes & development.

[42]  S. Moebus,et al.  Incorporation of fasting therapy in an integrative medicine ward: evaluation of outcome, safety, and effects on lifestyle adherence in a large prospective cohort study. , 2005, Journal of alternative and complementary medicine.

[43]  Michael D. George,et al.  A protein conjugation system essential for autophagy , 1998, Nature.

[44]  Daniel J Klionsky,et al.  Development by self-digestion: molecular mechanisms and biological functions of autophagy. , 2004, Developmental cell.

[45]  Caroline Palmeira-dos-Santos,et al.  Comparative study of autophagy inhibition by 3MA and CQ on Cytarabine-induced death of leukaemia cells , 2014, Journal of Cancer Research and Clinical Oncology.

[46]  F. Dai,et al.  Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/β-catenin signaling pathways in hepatocellular and colorectal carcinoma cells , 2016, Oncotarget.

[47]  M. Prescott,et al.  Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum , 2011, Autophagy.

[48]  D. Kong,et al.  Autophagy inhibition plays the synergetic killing roles with radiation in the multi-drug resistant SKVCR ovarian cancer cells , 2012, Radiation oncology.

[49]  A. Cuervo,et al.  Chaperone-mediated autophagy: a unique way to enter the lysosome world. , 2012, Trends in cell biology.

[50]  C. O’Flanagan,et al.  When less may be more: calorie restriction and response to cancer therapy , 2017, BMC Medicine.

[51]  Nektarios Tavernarakis,et al.  Regulation of autophagy by cytoplasmic p53 , 2008, Nature Cell Biology.

[52]  P. Conti,et al.  Fasting Enhances the Response of Glioma to Chemo- and Radiotherapy , 2012, PloS one.

[53]  Xiaohong Li,et al.  Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer , 2015, Molecular medicine reports.

[54]  Qingling Zhang,et al.  Resveratrol reverses Doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer , 2017, Journal of Experimental & Clinical Cancer Research.

[55]  D. Gewirtz The Challenge of Developing Autophagy Inhibition as a Therapeutic Strategy. , 2016, Cancer research.

[56]  Yong Liu,et al.  Metformin partially reverses the carboplatin-resistance in NSCLC by inhibiting glucose metabolism , 2017, Oncotarget.

[57]  Yuyuan Dai,et al.  Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma , 2016, Cellular and Molecular Neurobiology.

[58]  E. White,et al.  Autophagy and Tumor Metabolism. , 2017, Cell metabolism.

[59]  G. Bjørkøy,et al.  p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy* , 2007, Journal of Biological Chemistry.

[60]  Changhan Lee,et al.  Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy , 2008, Proceedings of the National Academy of Sciences.

[61]  L. Galluzzi,et al.  Autophagy and Mitophagy in Cardiovascular Disease. , 2017, Circulation research.

[62]  G. Kroemer,et al.  Caloric restriction mimetics: towards a molecular definition , 2014, Nature Reviews Drug Discovery.

[63]  P. Codogno,et al.  Autophagy, signaling and obesity. , 2012, Pharmacological research.

[64]  S. Smaili,et al.  The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy. , 2016, European journal of medicinal chemistry.

[65]  Safety and feasibility of fasting in combination with platinum-based chemotherapy , 2016, BMC Cancer.

[66]  B. Zhivotovsky,et al.  Caloric restriction - A promising anti-cancer approach: From molecular mechanisms to clinical trials. , 2017, Biochimica et biophysica acta. Reviews on cancer.

[67]  E. White,et al.  Recent insights into the function of autophagy in cancer , 2016, Genes & development.

[68]  Guido Kroemer,et al.  Autophagy and the integrated stress response. , 2010, Molecular cell.

[69]  A. Troxel,et al.  Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma , 2014, Autophagy.

[70]  N. Denko,et al.  Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L , 2008, Cell Death and Differentiation.

[71]  H. Hibshoosh,et al.  Induction of autophagy and inhibition of tumorigenesis by beclin 1 , 1999, Nature.

[72]  N. Mizushima,et al.  The role of Atg proteins in autophagosome formation. , 2011, Annual review of cell and developmental biology.

[73]  Daniel J Klionsky,et al.  Mammalian autophagy: core molecular machinery and signaling regulation. , 2010, Current opinion in cell biology.

[74]  A. K. Calgarotto,et al.  Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells. , 2016, European journal of medicinal chemistry.

[75]  J. Debnath,et al.  Autophagy at the crossroads of catabolism and anabolism , 2015, Nature Reviews Molecular Cell Biology.

[76]  M. Vinciguerra,et al.  Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy , 2017, PLoS biology.

[77]  Seamus J. Martin,et al.  Autophagy in malignant transformation and cancer progression , 2015, The EMBO journal.

[78]  Masaaki Komatsu,et al.  Autophagy: Renovation of Cells and Tissues , 2011, Cell.

[79]  E. White,et al.  Autophagy, stress, and cancer metabolism: what doesn't kill you makes you stronger. , 2011, Cold Spring Harbor symposia on quantitative biology.

[80]  Y. Eishi,et al.  Autophagy-deficient mice develop multiple liver tumors. , 2011, Genes & development.

[81]  J. Ha,et al.  Novel pharmacological modulators of autophagy: an updated patent review (2012-2015) , 2016, Expert opinion on therapeutic patents.

[82]  M. Matsui,et al.  In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. , 2003, Molecular biology of the cell.

[83]  P. Auberger,et al.  When autophagy meets cancer through p62/SQSTM1. , 2012, American journal of cancer research.

[84]  F. Ciccosanti,et al.  Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma , 2014, Cell Death and Differentiation.

[85]  Robert Pless,et al.  Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival , 2015, Proceedings of the National Academy of Sciences.

[86]  S. P. Andrews,et al.  Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities , 2017, Neuron.

[87]  Daniel J Klionsky,et al.  A unified nomenclature for yeast autophagy-related genes. , 2003, Developmental cell.

[88]  F. Di Virgilio,et al.  Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. , 2016, Cancer cell.

[89]  E. White,et al.  Autophagy suppresses tumor progression by limiting chromosomal instability. , 2007, Genes & development.

[90]  S. Smaili,et al.  Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death. , 2017, Biochemical and biophysical research communications.

[91]  Arnold J. Levine,et al.  Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[92]  P. Cohen,et al.  Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. , 2010, Cancer research.

[93]  S. Tsuboi,et al.  Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction , 1992, The Journal of cell biology.

[94]  James B. Mitchell,et al.  Caloric restriction augments radiation efficacy in breast cancer , 2013, Cell cycle.

[95]  S. Smaili,et al.  Interplay between apoptosis and autophagy, a challenging puzzle: new perspectives on antitumor chemotherapies. , 2013, Chemico-biological interactions.

[96]  Zhirong Sun,et al.  Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages , 2017, Oncotarget.