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Research Paper

A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis

, , , , , , , , & show all
Pages 1694-1718 | Received 11 Apr 2018, Accepted 10 Feb 2019, Published online: 08 Mar 2019

References

  • Mony VK, Benjamin S, O’Rourke EJ. A lysosome-centered view of nutrient homeostasis. Autophagy. 2016;12(4):619–631. PubMed PMID: 27050453; PubMed Central PMCID: PMC4836021
  • Galluzzi L, Bravo-San Pedro JM, Levine B, et al. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017 Jul;16(7):487–511. PubMed PMID: 28529316; PubMed Central PMCID: PMC5713640.
  • Yu L, Chen Y, Tooze SA, Autophagy pathway: cellular and molecular mechanisms. Autophagy. 2017 Sep 21:1–9. DOI:10.1080/15548627.2017.1378838 PubMed PMID: 28933638.
  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646–674. PubMed PMID: 21376230.
  • Gotink KJ, Broxterman HJ, Labots M, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011 Dec 1;17(23):7337–7346. PubMed PMID: 21980135; PubMed Central PMCID: PMC4461037.
  • Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017 Sep;17(9):528–542. PubMed PMID: 28751651.
  • Mulcahy Levy JM, Zahedi S, Griesinger AM, et al. Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors. Elife. 2017 Jan 17;6. PubMed PMID: 28094001; PubMed Central PMCID: PMC5241115.
  • Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, et al. The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer. Sci Rep. 2013;3:2469. PubMed PMID: 23965851; PubMed Central PMCID: PMC3749547.
  • Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol Ther. 1998 Jul;79(1):55–87. PubMed PMID: 9719345.
  • Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol. 2009 Dec 25;625(1–3):220–233. PubMed PMID: 19836374.
  • Goardon N, Marchi E, Atzberger A, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell. 2011 Jan 18;19(1):138–152. PubMed PMID: 21251617.
  • Yang S, Wang X, Contino G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011 Apr 01;25(7):717–729. PubMed PMID: 21406549; PubMed Central PMCID: PMC3070934.
  • Pellegrini P, Strambi A, Zipoli C, et al. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. Autophagy. 2014 Apr;10(4):562–571. PubMed PMID: 24492472; PubMed Central PMCID: PMC3984580.
  • Marino ML, Pellegrini P, Di Lernia G, et al. Autophagy is a protective mechanism for human melanoma cells under acidic stress. J Biol Chem. 2012 Aug 31;287(36):30664–30676. PubMed PMID: 22761435; PubMed Central PMCID: PMC3436311.
  • Piao S, Amaravadi RK. Targeting the lysosome in cancer. Ann N Y Acad Sci. 2016 May;1371(1):45–54. PubMed PMID: 26599426; PubMed Central PMCID: PMC4879098
  • Davidson SM, Vander Heiden MG. Critical functions of the lysosome in cancer biology. Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:481–507. PubMed PMID: 27732799.
  • Rebecca VW, Nicastri MC, McLaughlin N, et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discov. 2017 Nov;7(11):1266–1283. PubMed PMID: 28899863.
  • Lee CY, Johnson RL, Wichterman-Kouznetsova J, et al. High-throughput screening for genes that prevent excess DNA replication in human cells and for molecules that inhibit them. Methods. 2012 Jun;57(2):234–248. PubMed PMID: 22503772; PubMed Central PMCID: PMC4149752.
  • Zhu W, Lee CY, Johnson RL, et al. An image-based, high-throughput screening assay for molecules that induce excess DNA replication in human cancer cells. Mol Cancer Res. 2011 Mar;93:294–310. [pii]. PubMed PMID: 21257818; PubMed Central PMCID: PMC3060295. eng.
  • Chernomordik LV, Kozlov MM. Protein-lipid interplay in fusion and fission of biological membranes. Annu Rev Biochem. 2003;72:175–207. PubMed PMID: 14527322.
  • Jia R, Guardia CM, Pu J, et al. BORC coordinates encounter and fusion of lysosomes with autophagosomes. Autophagy. 2017 Oct 3;13(10):1648–1663. PubMed PMID: 28825857; PubMed Central PMCID: PMC5640200.
  • Pu J, Schindler C, Jia R, et al. BORC, a multisubunit complex that regulates lysosome positioning. Dev Cell. 2015 Apr 20;33(2):176–188. PubMed PMID: 25898167; PubMed Central PMCID: PMC4788105.
  • Niwa S, Tao L, Lu SY, et al. BORC regulates the axonal transport of synaptic vesicle precursors by activating ARL-8. Curr Biol. 2017 Sep 11;27(17):2569–2578 e4. PubMed PMID: 28823680; PubMed Central PMCID: PMC5693321.
  • Khatter D, Raina VB, Dwivedi D, et al. The small GTPase Arl8b regulates assembly of the mammalian HOPS complex on lysosomes. J Cell Sci. 2015 May 1;128(9):1746–1761. PubMed PMID: 25908847; PubMed Central PMCID: PMC4432227.
  • Pols MS, ten Brink C, Gosavi P, et al. The HOPS proteins hVps41 and hVps39 are required for homotypic and heterotypic late endosome fusion. Traffic. 2013 Feb;14(2):219–232. PubMed PMID: 23167963.
  • Orr A, Wickner W, Rusin SF, et al. Yeast vacuolar HOPS, regulated by its kinase, exploits affinities for acidic lipids and Rab: gTPfor membrane binding and to catalyze tethering and fusion. Mol Biol Cell. 2015 Jan 15;26(2):305–315. PubMed PMID: 25411340; PubMed Central PMCID: PMC4294677.
  • Martens S, McMahon HT. Mechanisms of membrane fusion: disparate players and common principles. Nat Rev Mol Cell Biol. 2008 Jul;9(7):543–556. PubMed PMID: 18496517.
  • Beckers CJ, Block MR, Glick BS, et al. Vesicular transport between the endoplasmic reticulum and the Golgi stack requires the NEM-sensitive fusion protein. Nature. 1989 Jun 1;339(6223):397–398. PubMed PMID: 2542798.
  • Wang T, Li L, Hong W. SNARE proteins in membrane trafficking. Traffic. 2017 Dec;18(12):767–775. PubMed PMID: 28857378.
  • Mindell JA. Lysosomal acidification mechanisms. Annu Rev Physiol. 2012;74:69–86. PubMed PMID: 22335796.
  • Ho CY, Choy CH, Wattson CA, et al. The Fab1/PIKfyve phosphoinositide phosphate kinase is not necessary to maintain the pH of lysosomes and of the yeast vacuole. J Biol Chem. 2015 Apr 10;290(15):9919–9928. PubMed PMID: 25713145; PubMed Central PMCID: PMC4392288.
  • Yapici NB, Bi Y, Li P, et al. Highly stable and sensitive fluorescent probes (LysoProbes) for lysosomal labeling and tracking. Sci Rep. 2015 Feb;26(5):8576. PubMed PMID: 25715948; PubMed Central PMCID: PMC4341211.
  • Maxson ME, Grinstein S. The vacuolar-type H(+)-ATPase at a glance - more than a proton pump. J Cell Sci. 2014 Dec 1;127(Pt 23):4987–4993. PubMed PMID: 25453113.
  • Chen CS, Chen WN, Zhou M, et al. Probing the cathepsin D using a BODIPY FL-pepstatin A: applications in fluorescence polarization and microscopy. J Biochem Biophys Methods. 2000 Mar 16;42(3):137–151. PubMed PMID: 10737220.
  • Thome MP, Filippi-Chiela EC, Villodre ES, et al. Ratiometric analysis of Acridine Orange staining in the study of acidic organelles and autophagy. J Cell Sci. 2016 Dec 15;129(24):4622–4632. PubMed PMID: 27875278.
  • Laurent-Matha V, Derocq D, Prebois C, et al. Processing of human cathepsin D is independent of its catalytic function and auto-activation: involvement of cathepsins L and B. J Biochem. 2006 Mar;139(3):363–371. PubMed PMID: 16567401; PubMed Central PMCID: PMC2376303.
  • Mizushima N, Yamamoto A, Hatano M, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol. 2001 Feb 19;152(4):657–668. PubMed PMID: 11266458; PubMed Central PMCID: PMC2195787.
  • Pfeifer U. Inhibition by insulin of the formation of autophagic vacuoles in rat liver. A morphometric approach to the kinetics of intracellular degradation by autophagy. J Cell Biol. 1978 Jul;78(1):152–167. PubMed PMID: 670291; PubMed Central PMCID: PMC2110173.
  • Schworer CM, Shiffer KA, Mortimore GE. Quantitative relationship between autophagy and proteolysis during graded amino acid deprivation in perfused rat liver. J Biol Chem. 1981 Jul 25;256(14):7652–7658. PubMed PMID: 7019210.
  • Li Z, Ji X, Wang D, et al. Autophagic flux is highly active in early mitosis and differentially regulated throughout the cell cycle. Oncotarget. 2016 Jun 28;7(26):39705–39718. PubMed PMID: 27213594; PubMed Central PMCID: PMC5129964.
  • Kimura S, Noda T, Yoshimori T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy. 2007 Sep–oct;3(5):452–460. PubMed PMID: 17534139.
  • Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet. 2002 May 01;11(9):1107–1117. PubMed PMID: 11978769.
  • Sarkar S, Ravikumar B, Floto RA, et al. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 2009 Jan;16(1):46–56. PubMed PMID: 18636076.
  • Mauvezin C, Nagy P, Juhasz G, et al. Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification. Nat Commun. 2015 May;11(6):7007. PubMed PMID: 25959678; PubMed Central PMCID: PMC4428688.
  • Mauvezin C, Neufeld TP. Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy. 2015;11(8):1437–1438. PubMed PMID: 26156798; PubMed Central PMCID: PMC4590655.
  • Luzio JP, Pryor PR, Bright NA. Lysosomes: fusion and function. Nat Rev Mol Cell Biol. 2007 Aug;8(8):622–632. PubMed PMID: 17637737.
  • Compton LM, Ikonomov OC, Sbrissa D, et al. Active vacuolar H+ ATPase and functional cycle of Rab5 are required for the vacuolation defect triggered by PtdIns(3,5)P2 loss under PIKfyve or Vps34 deficiency. Am J Physiol Cell Physiol. 2016 Sep 01;311(3):C366–C77. PubMed PMID: 27335171; PubMed Central PMCID: PMC5129759.
  • Davis MI, Hunt JP, Herrgard S, et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Nov;29(11):1046–1051. PubMed PMID: 22037378.
  • Ikonomov OC, Sbrissa D, Delvecchio K, et al. The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve± mice. J Biol Chem. 2011 Apr 15;286(15):13404–13413. PubMed PMID: 21349843; PubMed Central PMCID: PMC3075686.
  • Ikonomov OC, Sbrissa D, Shisheva A. Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion. Am J Physiol Cell Physiol. 2006 Aug;291(2):C393–C404. PubMed PMID: 16510848.
  • Sbrissa D, Ikonomov OC, Fu Z, et al. Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J Biol Chem. 2007 Aug 17;282(33):23878–23891. PubMed PMID: 17556371.
  • Shim H, Wu C, Ramsamooj S, et al. Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system. Proc Natl Acad Sci U S A. 2016 Jul 05;113(27):7596–7601. PubMed PMID: 27313209; PubMed Central PMCID: PMC4941458.
  • Mackey AM, Sarkes DA, Bettencourt I, et al. PIP4kgamma is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation. Sci Signal. 2014 Nov 4;7(350):ra104. PubMed PMID: 25372051; PubMed Central PMCID: PMC4579097.
  • Al-Ramahi I, Giridharan SSP, Chen YC, et al. Inhibition of PIP4Kgamma ameliorates the pathological effects of mutant huntingtin protein. Elife. 2017 Dec 26:6. DOI:10.7554/eLife.29123 PubMed PMID: 29256861; PubMed Central PMCID: PMC5743427.
  • Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009 Oct 15;122(Pt 20):3589–3594. PubMed PMID: 19812304; PubMed Central PMCID: PMC2758797.
  • Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Invest Drugs. 2002 Feb;3(2):295–304. PubMed PMID: 12020063.
  • Magnuson B, Ekim B, Fingar DC. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 2012 Jan 1;441(1):1–21. PubMed PMID: 22168436.
  • Strohecker AM, White E. Targeting mitochondrial metabolism by inhibiting autophagy in BRAF-driven cancers. Cancer Discov. 2014 Jul;4(7):766–772. PubMed PMID: 24860158; PubMed Central PMCID: PMC4090279.
  • Goodall ML, Wang T, Martin KR, et al. Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib. Autophagy. 2014 Jun;10(6):1120–1136. PubMed PMID: 24879157; PubMed Central PMCID: PMC4091172.
  • Akan P, Alexeyenko A, Costea PI, et al. Comprehensive analysis of the genome transcriptome and proteome landscapes of three tumor cell lines. Genome Med. 2012;4(11):86. PubMed PMID: 23158748; PubMed Central PMCID: PMC3580420.
  • Ikonomov OC, Sbrissa D, Shisheva A. Mammalian cell morphology and endocytic membrane homeostasis require enzymatically active phosphoinositide 5-kinase PIKfyve. J Biol Chem. 2001 Jul 13;276(28):26141–26147. PubMed PMID: 11285266.
  • de Lartigue J, Polson H, Feldman M, et al. PIKfyve regulation of endosome-linked pathways. Traffic. 2009 Jul;10(7):883–893. PubMed PMID: 19582903; PubMed Central PMCID: PMC2723830.
  • Gayle S, Landrette S, Beeharry N, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768–1778. PubMed PMID: 28104689.
  • Sano O, Kazetani K, Funata M, et al. Vacuolin-1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition. FEBS Lett. 2016 Jun;590(11):1576–1585. PubMed PMID: 27135648.
  • Jefferies HB, Cooke FT, Jat P, et al. A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding. EMBO Rep. 2008 Feb;9(2):164–170. PubMed PMID: 18188180; PubMed Central PMCID: PMC2246419.
  • Cai X, Xu Y, Cheung AK, et al. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol. 2013 Jul 25;20(7):912–921. PubMed PMID: 23890009; PubMed Central PMCID: PMC4878021.
  • Dove SK, Dong K, Kobayashi T, et al. Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. Biochem J. 2009 Apr 1;419(1):1–13. PubMed PMID: 19272020.
  • Nicot AS, Laporte J. Endosomal phosphoinositides and human diseases. Traffic. 2008 Aug;9(8):1240–1249. PubMed PMID: 18429927; PubMed Central PMCID: PMC2607523.
  • Shisheva A. PIKfyve: partners, significance, debates and paradoxes. Cell Biol Int. 2008 Jun;32(6):591–604. PubMed PMID: 18304842; PubMed Central PMCID: PMC2491398.
  • Hessvik NP, Overbye A, Brech A, et al. PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell Mol Life Sci. 2016 Dec;73(24):4717–4737. PubMed PMID: 27438886.
  • Demirsoy S, Martin S, Motamedi S, et al. ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated scaffolding function. Hum Mol Genet. 2017 May 1;26(9):1656–1669. PubMed PMID: 28334751.
  • Ho CY, Alghamdi TA, Botelho RJ. Phosphatidylinositol-3,5-bisphosphate: no longer the poor PIP2. Traffic. 2012 Jan;13(1):1–8. PubMed PMID: 21736686.
  • Jin N, Lang MJ, Weisman LS. Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time. Biochem Soc Trans. 2016 Feb;44(1):177–184. PubMed PMID: 26862203; PubMed Central PMCID: PMC4836390
  • Vicinanza M, Korolchuk VI, Ashkenazi A, et al. PI(5)P regulates autophagosome biogenesis. Mol Cell. 2015 Jan 22;57(2):219–234. PubMed PMID: 25578879; PubMed Central PMCID: PMC4306530.
  • Hasegawa J, Iwamoto R, Otomo T, et al. Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome. Embo J. 2016 Sep 1;35(17):1853–1867. PubMed PMID: 27340123; PubMed Central PMCID: PMC5007553.
  • Hasegawa J, Strunk BS, Weisman LS. PI5P and PI(3,5)P2: minor, but essential phosphoinositides. Cell Struct Funct. 2017 May 3;42(1):49–60. PubMed PMID: 28302928.
  • Yu L, McPhee CK, Zheng L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010 Jun 17;465(7300):942–946. PubMed PMID: 20526321; PubMed Central PMCID: PMC2920749.
  • Li X, Rydzewski N, Hider A, et al. A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol. 2016 Apr;18(4):404–417. PubMed PMID: 26950892; PubMed Central PMCID: PMC4871318.
  • Wartosch L, Gunesdogan U, Graham SC, et al. Recruitment of VPS33A to HOPS by VPS16 is required for lysosome fusion with endosomes and autophagosomes. Traffic. 2015 Jul;16(7):727–742. PubMed PMID: 25783203; PubMed Central PMCID: PMC4510706.
  • Vivona S, Cipriano DJ, O’Leary S, et al. Disassembly of all SNARE complexes by N-ethylmaleimide-sensitive factor (NSF) is initiated by a conserved 1:1 interaction between alpha-soluble NSF attachment protein (SNAP)and SNARE complex. J Biol Chem. 2013 Aug 23;288(34):24984–24991. PubMed PMID: 23836889; PubMed Central PMCID: PMC3750193.
  • Pu J, Guardia CM, Keren-Kaplan T, et al. Mechanisms and functions of lysosome positioning. J Cell Sci. 2016 Dec 1;129(23):4329–4339. PubMed PMID: 27799357; PubMed Central PMCID: PMC5201012.
  • Bissig C, Hurbain I, Raposo G, et al. PIKfyve activity regulates reformation of terminal storage lysosomes from endolysosomes. Traffic. 2017 Nov;18(11):747–757. PubMed PMID: 28857423.
  • Choy CH, Saffi G, Gray MA, et al. Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence. J Cell Sci. 2018 May 21;131(10). DOI:10.1242/jcs.213587 PubMed PMID: 29661845.
  • Lu Y, Dong S, Hao B, et al. Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A. Autophagy. 2014;10(11):1895–1905. PubMed PMID: 25483964; PubMed Central PMCID: PMC4502727.
  • Martin S, Harper CB, May LM, et al. Inhibition of PIKfyve by YM-201636 dysregulates autophagy and leads to apoptosis-independent neuronal cell death. PLoS One. 2013;8(3):e60152. PubMed PMID: 23544129; PubMed Central PMCID: PMC3609765.
  • Kim GH, Dayam RM, Prashar A, et al. PIKfyve inhibition interferes with phagosome and endosome maturation in macrophages. Traffic. 2014 Oct;15(10):1143–1163. PubMed PMID: 25041080.
  • Tsuruta F, Dolmetsch RE. PIKfyve mediates the motility of late endosomes and lysosomes in neuronal dendrites. Neurosci Lett. 2015 Sep 25;605:18–23. PubMed PMID: 26232680.
  • Baars TL, Petri S, Peters C, et al. Role of the V-ATPase in regulation of the vacuolar fission-fusion equilibrium. Mol Biol Cell. 2007 Oct;18(10):3873–3882. PubMed PMID: 17652457; PubMed Central PMCID: PMC1995711.
  • Walter C, Clemens LE, Muller AJ, et al. Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro. Neuropharmacology. 2016 Sep;108:24–38. PubMed PMID: 27133377.
  • Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013 Oct;13(10):722–737. PubMed PMID: 24064518; PubMed Central PMCID: PMC5340150.
  • Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017 May 2;25(5):1037–1043. PubMed PMID: 28467923; PubMed Central PMCID: PMC5604466.
  • Nyfeler B, Eng CH. Revisiting autophagy addiction of tumor cells. Autophagy. 2016 Jul 2;12(7):1206–1207. PubMed PMID: 27097231; PubMed Central PMCID: PMC4990994.
  • Mainz L, Rosenfeldt MT. Autophagy and cancer - insights from mouse models. FEBS J. 2017 Sep 16. DOI:10.1111/febs.14274 PubMed PMID: 28921866.
  • Mowers EE, Sharifi MN, Macleod KF. Autophagy in cancer metastasis. Oncogene. 2017 Mar 23;36(12):1619–1630. PubMed PMID: 27593926; PubMed Central PMCID: PMC5337449.
  • Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009 Jun 12;137(6):1062–1075. PubMed PMID: 19524509; PubMed Central PMCID: PMC2802318.
  • Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006 Jul;10(1):51–64. PubMed PMID: 16843265; PubMed Central PMCID: PMC2857533.
  • Liu XD, Yao J, Tripathi DN, et al. Autophagy mediates HIF2alpha degradation and suppresses renal tumorigenesis. Oncogene. 2015 May 7;34(19):2450–2460. PubMed PMID: 24998849; PubMed Central PMCID: PMC4286517.
  • Karantza-Wadsworth V, Patel S, Kravchuk O, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007 Jul 1;21(13):1621–1635. PubMed PMID: 17606641; PubMed Central PMCID: PMC1899472.
  • Chude CI, Amaravadi RK. Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int J Mol Sci. 2017 June 16;18(6). DOI:10.3390/ijms18061279 PubMed PMID: 28621712; PubMed Central PMCID:PMC5486101.
  • Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy. 2014 Aug;10(8):1391–1402. PubMed PMID: 24991838; PubMed Central PMCID: PMC4203516.
  • Xie X, Koh JY, Price S, et al. Atg7 overcomes senescence and promotes growth of brafV600E-driven melanoma. Cancer Discov. 2015 Apr;5(4):410–423. PubMed PMID: 25673642; PubMed Central PMCID: PMC4390491.
  • Saric A, Grinstein S, Freeman SA. Measurement of autolysosomal pH by dual-wavelength ratio imaging. Methods Enzymol. 2017;588:15–29. PubMed PMID: 28237098.
  • Ohkuma S, Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3327–3331. PubMed PMID: 28524; PubMed Central PMCID: PMC392768
  • Crowley LC, Christensen ME, Waterhouse NJ. Measuring survival of adherent cells with the colony-forming assay. Cold Spring Harb Protoc. 2016 Aug 1;2016(8). DOI:10.1101/pdb.prot087171 PubMed PMID: 27480717.

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