Abstract
Autophagy is a complex process that plays a central role in maintaining cellular homeostasis by breaking down macromolecules and utilizing the metabolites as energy. This allows cells to maintain efficient ATP levels and promote cell survival by recycling macromolecules or dysfunctional organelles. Macromolecule degradation takes place in the lysosome and is identified as macroautophagy, microautophagy, or chaperone-mediated autophagy. Autophagy is also activated in response to cellular nutrient starvation as low glucose levels will cause cells to break down amino acids, such as glutamine. Glutaminolysis is able to support the tricarboxylic acid (TCA) cycle and when cells undergo severe starvation they can produce adequate ATP and NADPH levels. The underlying mechanism of autophagy is regulated by specific genes, primarily known as autophagy-related genes (ATGs). Although autophagy is critical for normal cell maintenance, cancer cells utilize autophagy to eliminate the demanding metabolic stress that is put on the cells allowing them to continue to grow and divide. Cancers with elevated autophagy activity are able to regulate important proliferative signaling pathways, including the PI3K/AKT/mTOR. Mutations in tumor suppressor genes, KRAS, Tp53, BRCA2, and PTEN have demonstrated the ability to activate autophagy, allowing for further uncontrolled growth of cancers. Autophagy has dual effects; normal cells can utilize it to promote autophagic cell death under stressful conditions, while cancer cells use it to induce chemo-resistance, promote cellular growth and division even under stressful metabolic conditions. Patients that present with elevated genes associated with autophagy could benefit from pharmacological inhibition of autophagy and targeted therapies to those genes. Here, we complied the role of autophagy regulation in cancer and cancer cell metabolism.
Keywords
- Autophagy
- Metabolism
- Tumor microenvironment
- Chemotherapy
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13 March 2020
The following late corrections have been carried out in the updated version of chapters 6 and 7:
References
Amaravadi R, Kimmelman AC, White E (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30(17):1913–1930
Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117(2):326–336
Ambrogio C, Nadal E, Villanueva A, Gomez-Lopez G, Cash TP, Barbacid M, Santamaria D (2016) KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy. ESMO Open 1(5):e000076
Amin AD, Peters TL, Li L, Rajan SS, Choudhari R, Puvvada SD, Schatz JH (2017) Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Cold Spring Harb Mol Case Stud 3(3):a001719
Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Vander Heiden MG (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8(10):839–847
Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P, Ogier-Denis E (2001) The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276(38):35243–35246
Arif M, Vedamurthy BM, Choudhari R, Ostwal YB, Mantelingu K, Kodaganur GS, Kundu TK (2010) Nitric oxide-mediated histone hyperacetylation in oral cancer: target for a water-soluble HAT inhibitor, CTK7A. Chem Biol 17(8):903–913
Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R, Bucala R (2002) High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 62(20):5881–5887
Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182(4):685–701
Ayllon V, O’Connor R (2007) PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response. Oncogene 26(24):3451–3461
Bahrami F, Pourgholami MH, Mekkawy AH, Rufener L, Morris DL (2014) Monepantel induces autophagy in human ovarian cancer cells through disruption of the mTOR/p70S6K signalling pathway. Am J Cancer Res 4(5):558–571
Bai H, Li H, Li W, Gui T, Yang J, Cao D, Shen K (2015) The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget 6(28):25520–25532
Ben-Josef E, Lawrence TS (2008) Chemoradiotherapy for unresectable pancreatic cancer. Int J Clin Oncol 13(2):121–126
Bertolo C, Roa S, Sagardoy A, Mena-Varas M, Robles EF, Martinez-Ferrandis JI, Sagaert X, Tousseyn T, Orta A, Lossos IS, Amar S, Natkunam Y, Briones J, Melnick A, Malumbres R, Martinez-Climent JA (2013) LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. Br J Haematol 162(5):621–630
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424
Cagnol S, Chambard JC (2010) ERK and cell death: mechanisms of ERK-induced cell death—apoptosis, autophagy and senescence. FEBS J 277(1):2–21
Cai M, Hu Z, Liu J, Gao J, Liu C, Liu D, Tan M, Zhang D, Lin B (2014) Beclin 1 expression in ovarian tissues and its effects on ovarian cancer prognosis. Int J Mol Sci 15(4):5292–5303
Camacho CV, Choudhari R, Gadad SS (2018) Long noncoding RNAs and cancer, an overview. Steroids 133:93–95
Chang M (2012) Tamoxifen resistance in breast cancer. Biomol Ther (Seoul) 20(3):256–267
Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma—animal models and therapeutic challenges. Brain Pathol 19(1):112–120
Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G (2008) The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 8(1):11–23
Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368(7):651–662
Choudhari R, Minero VG, Menotti M, Pulito R, Brakebusch C, Compagno M, Voena C, Ambrogio C, Chiarle R (2016) Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice. Blood 127(10):1297–1306
Choudhari R, Sedano MJ, Harrison AL, Subramani R, Lin KY, Ramos EI, Lakshmanaswamy R, Gadad SS (2019) Long noncoding RNAs in cancer: from discovery to therapeutic targets. Adv Clin Chem. https://doi.org/10.1016/bs.acc.2019.08.003
Colombo MI (2007) Autophagy: a pathogen driven process. IUBMB Life 59(4–5):238–242
Cook KL, Shajahan AN, Warri A, Jin L, Hilakivi-Clarke LA, Clarke R (2012) Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res 72(13):3337–3349
Correa RJ, Valdes YR, Shepherd TG, DiMattia GE (2015) Beclin-1 expression is retained in high-grade serous ovarian cancer yet is not essential for autophagy induction in vitro. J Ovarian Res 8:52
Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24(1):92–104
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10(1):51–64
Ding LY, Chu M, Jiao YS, Hao Q, Xiao P, Li HH, Guo Q, Wang YD (2018) TFDP3 regulates the apoptosis and autophagy in breast cancer cell line MDA-MB-231. PLoS One 13(9):e0203833
Eberhardy SR, Farnham PJ (2001) c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. J Biol Chem 276(51):48562–48571
Eskelinen EL (2019) Autophagy: supporting cellular and organismal homeostasis by self-eating. Int J Biochem Cell Biol 111:1–10
Ettinger DS, Akerley W, Borghaei H, Chang AC, Cheney RT, Chirieac LR, D’Amico TA, Demmy TL, Govindan R, Grannis FW Jr, Grant SC, Horn L, Jahan TM, Komaki R, Kong FM, Kris MG, Krug LM, Lackner RP, Lennes IT, Loo BW Jr, Martins R, Otterson GA, Patel JD, Pinder-Schenck MC, Pisters KM, Reckamp K, Riely GJ, Rohren E, Shapiro TA, Swanson SJ, Tauer K, Wood DE, Yang SC, Gregory K, Hughes M, National Comprehensive Cancer (2013) Non-small cell lung cancer, version 2.2013. J Natl Compr Cancer Netw 11(6):645–653; quiz 653
Felippe Goncalves-de-Albuquerque C, Ribeiro Silva A, Ignacio da Silva C, Caire Castro-Faria-Neto H, Burth P (2017) Na/K pump and beyond: Na/K-ATPase as a modulator of apoptosis and autophagy. Molecules 22(4). https://doi.org/10.3390/molecules22040578
Friedberg JW (2017) How I treat double-hit lymphoma. Blood 130(5):590–596
Funderburk SF, Wang QJ, Yue Z (2010) The Beclin 1-VPS34 complex—at the crossroads of autophagy and beyond. Trends Cell Biol 20(6):355–362
Galluzzi L, Vicencio JM, Kepp O, Tasdemir E, Maiuri MC, Kroemer G (2008) To die or not to die: that is the autophagic question. Curr Mol Med 8(2):78–91
Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, Messa C, Guerra L, Giudici G, Sala E, Mussolin L, Deeren D, King MH, Steurer M, Ordemann R, Cohen AM, Grube M, Bernard L, Chiriano G, Antolini L, Piazza R (2014) Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst 106(2):djt378
Germic N, Frangez Z, Yousefi S, Simon HU (2019) Regulation of the innate immune system by autophagy: monocytes, macrophages, dendritic cells and antigen presentation. Cell Death Differ 26(4):715–727
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25(5):460–470
Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, Chen G, Price S, Lu W, Teng X, Snyder E, Santanam U, Dipaola RS, Jacks T, Rabinowitz JD, White E (2013) Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 27(13):1447–1461
Hamurcu Z, Delibasi N, Gecene S, Sener EF, Donmez-Altuntas H, Ozkul Y, Canatan H, Ozpolat B (2018) Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin beta1/ Src signaling in triple negative breast cancer cells. J Cancer Res Clin Oncol 144(3):415–430
Han Y, Fan S, Qin T, Yang J, Sun Y, Lu Y, Mao J, Li L (2018) Role of autophagy in breast cancer and breast cancer stem cells (Review). Int J Oncol 52(4):1057–1070
He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43(1):67–93
Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, Ngan HY, Pecorelli S, Beller U (2006) Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 95(Suppl 1):S161–S192
Hinzman CP, Aljehane L, Brown-Clay JD, Kallakury B, Sonahara F, Goel A, Trevino J, Banerjee PP (2018) Aberrant expression of PDZ-binding kinase/T-LAK cell-originated protein kinase modulates the invasive ability of human pancreatic cancer cells via the stabilization of oncoprotein c-MYC. Carcinogenesis 39(12):1548–1559
Huang JJ, Zhu YJ, Lin TY, Jiang WQ, Huang HQ, Li ZM (2011) Beclin 1 expression predicts favorable clinical outcome in patients with diffuse large B-cell lymphoma treated with R-CHOP. Hum Pathol 42(10):1459–1466
Iwadate R, Inoue J, Tsuda H, Takano M, Furuya K, Hirasawa A, Aoki D, Inazawa J (2014) High expression of SQSTM1/p62 protein is associated with poor prognosis in epithelial ovarian cancer. Acta Histochem Cytochem 47(6):295–301
Janku F, McConkey DJ, Hong DS, Kurzrock R (2011) Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 8(9):528–539
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300
Joel M, Mughal AA, Grieg Z, Murrell W, Palmero S, Mikkelsen B, Fjerdingstad HB, Sandberg CJ, Behnan J, Glover JC, Langmoen IA, Stangeland B (2015) Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo. Mol Cancer 14:121
Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T (2001) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410(6832):1111–1116
Kaza N, Kohli L, Roth KA (2012) Autophagy in brain tumors: a new target for therapeutic intervention. Brain Pathol 22(1):89–98
Kiffin R, Christian C, Knecht E, Cuervo AM (2004) Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 15(11):4829–4840
Kim JY, Cho CH, Song HS (2017) Targeted therapy of ovarian cancer including immune check point inhibitor. Korean J Intern Med 32(5):798–804
Kim KW, Hwang M, Moretti L, Jaboin JJ, Cha YI, Lu B (2008) Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 4(5):659–668
Kimmelman AC, White E (2017) Autophagy and tumor metabolism. Cell Metab 25(5):1037–1043
Klarer AC, O’Neal J, Imbert-Fernandez Y, Clem A, Ellis SR, Clark J, Clem B, Chesney J, Telang S (2014) Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism. Cancer Metab 2(1):2
Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, Jemal A, Anderson RN, Ajani UA, Edwards BK (2011) Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 103(9):714–736
Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5(9):726–734
Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H, Slamon DJ (2003) Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 95(2):142–153
Kong D, Ma S, Liang B, Yi H, Zhao Y, Xin R, Cui L, Jia L, Liu X, Liu X (2012) The different regulatory effects of p53 status on multidrug resistance are determined by autophagy in ovarian cancer cells. Biomed Pharmacother 66(4):271–278
Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A 105(9):3374–3379
Lee MH, Koh D, Na H, Ka NL, Kim S, Kim HJ, Hong S, Shin YK, Seong JK, Lee MO (2018) MTA1 is a novel regulator of autophagy that induces tamoxifen resistance in breast cancer cells. Autophagy 14(5):812–824
Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42
Li YJ, Lei YH, Yao N, Wang CR, Hu N, Ye WC, Zhang DM, Chen ZS (2017) Autophagy and multidrug resistance in cancer. Chin J Cancer 36(1):52
Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363(9414):1049–1057
Li Y, Zhou X, Zhang Y, Yang J, Xu Y, Zhao Y, Wang X (2019) CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma. Cell Cycle 18(4):379–394
Lin Y, Kuang W, Wu B, Xie C, Liu C, Tu Z (2017) IL-12 induces autophagy in human breast cancer cells through AMPK and the PI3K/Akt pathway. Mol Med Rep 16(4):4113–4118
Lin J, Xia L, Liang J, Han Y, Wang H, Oyang L, Tan S, Tian Y, Rao S, Chen X, Tang Y, Su M, Luo X, Wang Y, Wang H, Zhou Y, Liao Q (2019) The roles of glucose metabolic reprogramming in chemo- and radio-resistance. J Exp Clin Cancer Res 38(1):218
Liu C, Sun L, Yang J, Liu T, Yang Y, Kim SM, Ou X, Wang Y, Sun L, Zaidi M, New MI, Yuen T, Guo Q (2018) FSIP1 regulates autophagy in breast cancer. Proc Natl Acad Sci U S A 115(51):13075–13080
Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, Debnath J (2011) Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell 22(2):165–178
Lohinai Z, Klikovits T, Moldvay J, Ostoros G, Raso E, Timar J, Fabian K, Kovalszky I, Kenessey I, Aigner C, Renyi-Vamos F, Klepetko W, Dome B, Hegedus B (2017) KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep 7:39721
Lozy F, Karantza V (2012) Autophagy and cancer cell metabolism. Semin Cell Dev Biol 23(4):395–401
Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, Liao WS, Bast RC Jr (2008) The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest 118(12):3917–3929
Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li Z, Xu Y, Wang G, Huang Y, Xiong Y, Guan KL, Lei QY (2011) Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 42(6):719–730
Ma R, Li X, Liu H, Jiang R, Yang M, Zhang M, Wang Y, Zhao Y, Li H (2019a) GATA6-upregulating autophagy promotes TKI resistance in nonsmall cell lung cancer. Cancer Biol Ther 20(9):1206–1212
Ma H, Li Y, Wang X, Wu H, Qi G, Li R, Yang N, Gao M, Yan S, Yuan C, Kong B (2019b) PBK, targeted by EVI1, promotes metastasis and confers cisplatin resistance through inducing autophagy in high-grade serous ovarian carcinoma. Cell Death Dis 10(3):166
Ma L, Maruwge W, Strambi A, D’Arcy P, Pellegrini P, Kis L, de Milito A, Lain S, Brodin B (2014) SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth. Cell Death Dis 5:e1483
Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6(6):458–471
Mannava S, Grachtchouk V, Wheeler LJ, Im M, Zhuang D, Slavina EG, Mathews CK, Shewach DS, Nikiforov MA (2008) Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle 7(15):2392–2400
Marzec M, Kasprzycka M, Liu X, El-Salem M, Halasa K, Raghunath PN, Bucki R, Wlodarski P, Wasik MA (2007) Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. Oncogene 26(38):5606–5614
McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, Zhou W, Choi HG, Smith SL, Dowell L, Ulkus LE, Kuhlmann G, Greninger P, Christensen JG, Haber DA, Settleman J (2008) Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 68(9):3389–3395
Menotti M, Ambrogio C, Cheong TC, Pighi C, Mota I, Cassel SH, Compagno M, Wang Q, Dall’Olio R, Minero VG, Poggio T, Sharma GG, Patrucco E, Mastini C, Choudhari R, Pich A, Zamo A, Piva R, Giliani S, Mologni L, Collings CK, Kadoch C, Gambacorti-Passerini C, Notarangelo LD, Anton IM, Voena C, Chiarle R (2019) Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma. Nat Med 25(1):130–140
Mitou G, Frentzel J, Desquesnes A, Le Gonidec S, AlSaati T, Beau I, Lamant L, Meggetto F, Espinos E, Codogno P, Brousset P, Giuriato S (2015) Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma. Oncotarget 6(30):30149–30164
Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741
Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075
Monk BJ, Coleman RL (2009) Changing the paradigm in the treatment of platinum-sensitive recurrent ovarian cancer: from platinum doublets to nonplatinum doublets and adding antiangiogenesis compounds. Int J Gynecol Cancer 19(Suppl 2):S63–S67
Mu N, Lei Y, Wang Y, Wang Y, Duan Q, Ma G, Liu X, Su L (2019) Inhibition of SIRT1/2 upregulates HSPA5 acetylation and induces pro-survival autophagy via ATF4-DDIT4-mTORC1 axis in human lung cancer cells. Apoptosis 4(9–10):798–811
Murakami T, Nishiyama T, Shirotani T, Shinohara Y, Kan M, Ishii K, Kanai F, Nakazuru S, Ebina Y (1992) Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes. J Biol Chem 267(13):9300–9306
Nagelkerke A, Sieuwerts AM, Bussink J, Sweep FC, Look MP, Foekens JA, Martens JW, Span PN (2014) LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy. Endocr Relat Cancer 21(1):101–112
Nicotra G, Mercalli F, Peracchio C, Castino R, Follo C, Valente G, Isidoro C (2010) Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas. Mod Pathol 23(7):937–950
Oh S, Xiaofei E, Ni D, Pirooz SD, Lee JY, Lee D, Zhao Z, Lee S, Lee H, Ku B, Kowalik T, Martin SE, Oh BH, Jung JU, Liang C (2011) Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis. Cell Death Differ 18(3):452–464
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275(29):21797–21800
Pandareesh MD, Kandikattu HK, Razack S, Amruta N, Choudhari R, Vikram A, Doddapattar P (2018) Nutrition and nutraceuticals in neuroinflammatory and brain metabolic stress: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 17(9):680–688
Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23(1):27–47
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N (2015) Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524(7565):361–365
Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB, Gorski SM (2008) Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat 112(3):389–403
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112(12):1809–1820
Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN, Gilpin C, Levine B (2007) Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128(5):931–946
Racanelli AC, Kikkers SA, Choi AMK, Cloonan SM (2018) Autophagy and inflammation in chronic respiratory disease. Autophagy 14(2):221–232
Ren YA, Mullany LK, Liu Z, Herron AJ, Wong KK, Richards JS (2016) Mutant p53 promotes epithelial ovarian cancer by regulating tumor differentiation, metastasis, and responsiveness to steroid hormones. Cancer Res 76(8):2206–2218
Rikiishi H (2010) Possible role of autophagy in the treatment of pancreatic cancer with histone deacetylase inhibitors. Cancers (Basel) 2(4):2026–2043
Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S (2014) Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell 53(4):521–533
Rosenfeldt MT, O’Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, Ryan KM (2013) p53 status determines the role of autophagy in pancreatic tumour development. Nature 504(7479):296–300
Ryan DP, Hong TS, Bardeesy N (2014) Pancreatic adenocarcinoma. N Engl J Med 371(11):1039–1049
Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20(1):131–139
Samaddar JS, Gaddy VT, Duplantier J, Thandavan SP, Shah M, Smith MJ, Browning D, Rawson J, Smith SB, Barrett JT, Schoenlein PV (2008) A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol Cancer Ther 7(9):2977–2987
Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56
Shandilya J, Swaminathan V, Gadad SS, Choudhari R, Kodaganur GS, Kundu TK (2009) Acetylated NPM1 localizes in the nucleoplasm and regulates transcriptional activation of genes implicated in oral cancer manifestation. Mol Cell Biol 29(18):5115–5127
Shen Y, Li DD, Wang LL, Deng R, Zhu XF (2008) Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy 4(8):1067–1068
Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, Chen SJ, Chen Y, Zhao WL (2012) Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis 3:e275
Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306(5698):990–995
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34
Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496(7443):101–105
Strohecker AM, Guo JY, Karsli-Uzunbas G, Price SM, Chen GJ, Mathew R, McMahon M, White E (2013) Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov 3(11):1272–1285
Sun M, Gadad SS, Kim DS, Kraus WL (2015) Discovery, annotation, and functional analysis of long noncoding RNAs controlling cell-cycle gene expression and proliferation in breast cancer cells. Mol Cell 59(4):698–711
Sun H, Huang Z, Sheng W, Xu MD (2018a) Emerging roles of long non-coding RNAs in tumor metabolism. J Hematol Oncol 11(1):106
Sun WL, Wang L, Luo J, Zhu HW, Cai ZW (2018b) Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12. Cancer Sci 109(10):3129–3138
Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, Kyotani K, Mizowaki T, Imahori T, Ejima Y, Masui K, Gini B, Yang H, Hosoda K, Sasaki R, Mischel PS, Kohmura E (2015) Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J Clin Invest 125(4):1591–1602
Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M, Wolf DH (1994) Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 349(2):275–280
Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68(4):284–296
Trenti A, Grumati P, Cusinato F, Orso G, Bonaldo P, Trevisi L (2014) Cardiac glycoside ouabain induces autophagic cell death in non-small cell lung cancer cells via a JNK-dependent decrease of Bcl-2. Biochem Pharmacol 89(2):197–209
True O, Matthias P (2012) Interplay between histone deacetylases and autophagy—from cancer therapy to neurodegeneration. Immunol Cell Biol 90(1):78–84
Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff D (2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22(8):1430–1438
Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033
Vander Heiden MG, DeBerardinis RJ (2017) Understanding the intersections between metabolism and cancer biology. Cell 168(4):657–669
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Cancer Genome Atlas Research Network (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110
Wang C, Jiang J, Ji J, Cai Q, Chen X, Yu Y, Zhu Z, Zhang J (2017a) PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. Sci Rep 7(1):2886
Wang M, Zhang J, Huang Y, Ji S, Shao G, Feng S, Chen D, Zhao K, Wang Z, Wu A (2017b) Cancer-associated fibroblasts autophagy enhances progression of triple-negative breast cancer cells. Med Sci Monit 23:3904–3912
Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30(6):678–688
Weinberg SE, Chandel NS (2015) Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 11(1):9–15
Wen ZP, Zeng WJ, Chen YH, Li H, Wang JY, Cheng Q, Yu J, Zhou HH, Liu ZZ, Xiao J, Chen XP (2019) Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux. J Exp Clin Cancer Res 38(1):298
White E (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12(6):401–410
Williams T, Forsberg LJ, Viollet B, Brenman JE (2009) Basal autophagy induction without AMP-activated protein kinase under low glucose conditions. Autophagy 5(8):1155–1165
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 105(48):18782–18787
Wojtkowiak JW, Rothberg JM, Kumar V, Schramm KJ, Haller E, Proemsey JB, Lloyd MC, Sloane BF, Gillies RJ (2012) Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Res 72(16):3938–3947
Xu L, Zhang X, Li Y, Lu S, Lu S, Li J, Wang Y, Tian X, Wei JJ, Shao C, Liu Z (2016) Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/ JNK activation. Tumour Biol 37(7):8721–8729
Yan J, Zhang J, Zhang X, Li X, Li L, Li Z, Chen R, Zhang L, Wu J, Wang X, Sun Z, Fu X, Chang Y, Nan F, Yu H, Wu X, Feng X, Li W, Zhang M (2018) AEG-1 is involved in hypoxia-induced autophagy and decreases chemosensitivity in T-cell lymphoma. Mol Med 24(1):35
Yang ZJ, Chee CE, Huang S, Sinicrope FA (2011a) The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 10(9):1533–1541
Yang S, Imamura Y, Jenkins RW, Canadas I, Kitajima S, Aref A, Brannon A, Oki E, Castoreno A, Zhu Z, Thai T, Reibel J, Qian Z, Ogino S, Wong KK, Baba H, Kimmelman AC, Pasca Di Magliano M, Barbie DA (2016) Autophagy inhibition dysregulates TBK1 signaling and promotes pancreatic inflammation. Cancer Immunol Res 4(6):520–530
Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC, Von Hoff DD, Maitra A, Kimmelman AC (2014) Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov 4(8):905–913
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell’antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC (2011b) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25(7):717–729
Ying H, Qu D, Liu C, Ying T, Lv J, Jin S, Xu H (2015) Chemoresistance is associated with Beclin-1 and PTEN expression in epithelial ovarian cancers. Oncol Lett 9(4):1759–1763
Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA (2016) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30(4):355–385
Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14
Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304(5676):1500–1502
Zhan L, Zhang Y, Wang W, Song E, Fan Y, Li J, Wei B (2016) Autophagy as an emerging therapy target for ovarian carcinoma. Oncotarget 7(50):83476–83487
Zhang L, Ma T, Brozick J, Babalola K, Budiu R, Tseng G, Vlad AM (2016) Effects of Kras activation and Pten deletion alone or in combination on MUC1 biology and epithelial-to-mesenchymal transition in ovarian cancer. Oncogene 35(38):5010–5020
Zhang Q, Zhang Y, Zhang P, Chao Z, Xia F, Jiang C, Zhang X, Jiang Z, Liu H (2014) Hexokinase II inhibitor, 3-BrPA induced autophagy by stimulating ROS formation in human breast cancer cells. Genes Cancer 5(3–4):100–112
Zi D, Zhou ZW, Yang YJ, Huang L, Zhou ZL, He SM, He ZX, Zhou SF (2015) Danusertib induces apoptosis, cell cycle arrest, and autophagy but inhibits epithelial to mesenchymal transition involving PI3K/Akt/mTOR signaling pathway in human ovarian cancer cells. Int J Mol Sci 16(11):27228–27251
Acknowledgments
S.S.G. is supported by a first-time faculty recruitment award from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020).
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Pedroza, D.A. et al. (2020). Role of Autophagy in Cancer Cell Metabolism. In: Kumar, D. (eds) Cancer Cell Metabolism: A Potential Target for Cancer Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-15-1991-8_6
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