Abstract
Autophagy is a self-degradation process in which the cytoplasmic cargoes are delivered to the lysosomes for degradation. As the cargoes are degraded/recycled, the autophagy process maintains the cellular homeostasis. Anti-cancer therapies induce apoptosis and autophagy concomitantly, and the induced autophagy normally prevents stress responses that are being induced. In such cases, the inhibition of autophagy can be a reasonable strategy to enhance the efficacy of anti-cancer therapies. However, recent studies have shown that autophagy induced by anti-cancer drugs causes cell death/apoptosis induction, indicating a controversial role of autophagy in cancer cell survival or death/apoptosis. Therefore, in the present review, we aimed to assess the signaling mechanisms involved in autophagy and cell death/apoptosis induction during anti-cancer therapies. This review summarizes the process of autophagy, autophagy flux and its blockade, and measurement and interpretation of autophagy flux. Further, it describes the signaling pathways involved in the blockade of autophagy flux and the role of signaling molecules accumulated by autophagy blockade in cell death/apoptosis in various cancer cells during anti-cancer therapies. Altogether, it implies that factors such as types of cancer, drug therapies, and characteristics of autophagy should be evaluated before targeting autophagy for cancer treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Azimee S, Rahmati M, Fahimi H, Moosavi MA (2020) TiO2 nanoparticles enhance the chemotherapeutic effects of 5-fluorouracil in human AGS gastric cancer cells via autophagy blockade. Life Sci 248:117466. https://doi.org/10.1016/j.lfs.2020.117466
Ballabio A, Bonifacino JS (2020) Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol 21(2):101–118. https://doi.org/10.1038/s41580-019-0185-4
Bell BD, Leverrier S, Weist BM, Newton RH, Arechiga AF, Luhrs KA, Morrissette NS, Walsh CM (2008) FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proc Natl Acad Sci USA 105(43):16677–16682. https://doi.org/10.1073/pnas.0808597105
Bhattacharjee A, Hasanain M, Kathuria M, Singh A, Datta D, Sarkar J, Mitra KJ Sr (2018) Ormeloxifene-induced unfolded protein response contributes to autophagy-associated apoptosis via disruption of Akt/mTOR and activation of JNK. Sci Rep 8(1):1–13. https://doi.org/10.1038/s41598-018-20541-8
Cabukusta B, Neefjes J (2018) Mechanisms of lysosomal positioning and movement. Traffic 19(10):761–769. https://doi.org/10.1111/tra.12587
Cai H, Reinisch K, Ferro-Novick S (2007) Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev Cell 12(5):671–682. https://doi.org/10.1016/j.devcel.2007.04.005
Chang M, Song X, Geng X, Wang X, Wang W, Chen TC, Xie L, Song X (2018) Temozolomide–perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation. J Exp Clin Cancer Res 37(1):250. https://doi.org/10.1186/s13046-018-0905-1
Chang C-H, Bijian K, Wernic D, Su J, da Silva SD, Yu H, Qiu D, Asslan M, Alaoui-Jamali MA (2019) A novel orally available seleno-purine molecule suppresses triple-negative breast cancer cell proliferation and progression to metastasis by inducing cytostatic autophagy. Autophagy 15(8):1376–1390. https://doi.org/10.1080/15548627.2019.1582951
Chen Y, Azad MB, Gibson SB (2010) Methods for detecting autophagy and determining autophagy-induced cell death. Can J Physiol Pharmacol 88(3):285–295. https://doi.org/10.1139/Y10-010
Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Beninca C, Viscomi C, Zeviani M (2018) Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. EMBO Mol Med. https://doi.org/10.15252/emmm.201708799
Colacurcio DJ, Nixon RA (2016) Disorders of lysosomal acidification-the emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75–88. https://doi.org/10.1016/j.arr.2016.05.004
Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz LM, Li J, Vivona S, Pfuetzner RA, Brunger AT, Zhong Q (2015) ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520(7548):563–566. https://doi.org/10.1038/nature14147
du Toit A, Hofmeyr JS, Gniadek TJ, Loos B (2018) Measuring autophagosome flux. Autophagy 14(6):1060–1071. https://doi.org/10.1080/15548627.2018.1469590 (Epub 20 July 2018)
Dupont N, Orhon I, Bauvy C, Codogno P (2014) Autophagy and autophagic flux in tumor cells. Methods Enzymol 543:73–88. https://doi.org/10.1016/B978-0-12-801329-8.00004-0
Eskelinen EL (2005) Maturation of autophagic vacuoles in mammalian cells. Autophagy 1(1):1–10. https://doi.org/10.4161/auto.1.1.1270
Feng X, Chen L, Guo W, Zhang Y, Lai X, Shao L, Li Y (2018a) Graphene oxide induces p62/SQSTM-dependent apoptosis through the impairment of autophagic flux and lysosomal dysfunction in PC12 cells. Acta Biomater 81:278–292. https://doi.org/10.1016/j.actbio.2018.09.057
Feng X, Zhou J, Li J, Hou X, Li L, Chen Y, Fu S, Zhou L, Li C, Lei Y (2018b) Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function. Cell Death Dis 9(11):1117. https://doi.org/10.1038/s41419-018-1151-3
Folts CJ, Scott-Hewitt N, Proschel C, Mayer-Proschel M, Noble M (2016) Lysosomal re-acidification prevents lysosphingolipid-induced lysosomal impairment and cellular toxicity. PLoS Biol 14(12):e1002583. https://doi.org/10.1371/journal.pbio.1002583
Fujita N, Huang W, Lin TH, Groulx JF, Jean S, Nguyen J, Kuchitsu Y, Koyama-Honda I, Mizushima N, Fukuda M, Kiger AA (2017) Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy. Elife. https://doi.org/10.7554/eLife.23367
Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, Harper JW, Jaattela M, Johansen T, Juhasz G, Kimmelman AC, Kraft C, Ktistakis NT, Kumar S, Levine B, Lopez-Otin C, Madeo F, Martens S, Martinez J, Melendez A, Mizushima N, Munz C, Murphy LO, Penninger JM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Santambrogio L, Scorrano L, Simon AK, Simon HU, Simonsen A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Kroemer G (2017) Molecular definitions of autophagy and related processes. EMBO J 36(13):1811–1836. https://doi.org/10.15252/embj.201796697
Ganley IG (2013) Autophagosome maturation and lysosomal fusion. Essays Biochem 55:65–78. https://doi.org/10.1042/bse0550065
Guo B, Liang Q, Li L, Hu Z, Wu F, Zhang P, Ma Y, Zhao B, Kovacs AL, Zhang Z, Feng D, Chen S, Zhang H (2014) O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nat Cell Biol 16(12):1215–1226. https://doi.org/10.1038/ncb3066
Haspel J, Shaik RS, Ifedigbo E, Nakahira K, Dolinay T, Englert JA, Choi AM (2011) Characterization of macroautophagic flux in vivo using a leupeptin-based assay. Autophagy 7(6):629–642. https://doi.org/10.4161/auto.7.6.15100
Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C, Farkas T, Lopez-Rivas A, Jaattela M (2009) TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28(6):677–685. https://doi.org/10.1038/emboj.2009.8
Hu L, Jiang K, Ding C, Meng S (2017) Targeting autophagy for oncolytic immunotherapy. Biomedicines. https://doi.org/10.3390/biomedicines5010005
Huang A-C, Lien J-C, Lin M-W, Yang J-S, Wu P-P, Chang S-J, Lai T-Y (2013) Tetrandrine induces cell death in SAS human oral cancer cells through caspase activation-dependent apoptosis and LC3-I and LC3-II activation-dependent autophagy. Int J Oncol 43(2):485–494. https://doi.org/10.3892/ijo.2013.1952
Huynh KK, Eskelinen EL, Scott CC, Malevanets A, Saftig P, Grinstein S (2007) LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J 26(2):313–324. https://doi.org/10.1038/sj.emboj.7601511
Itakura E, Kishi-Itakura C, Mizushima N (2012) The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151(6):1256–1269. https://doi.org/10.1016/j.cell.2012.11.001
Iurlaro R, Munoz-Pinedo C (2016) Cell death induced by endoplasmic reticulum stress. FEBS J 283(14):2640–2652. https://doi.org/10.1111/febs.13598
Iwai-Kanai E, Yuan H, Huang C, Sayen MR, Perry-Garza CN, Kim L, Gottlieb RA (2008) A method to measure cardiac autophagic flux in vivo. Autophagy 4(3):322–329. https://doi.org/10.4161/auto.5603
Jean S, Cox S, Nassari S, Kiger AA (2015) Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome–lysosome fusion. EMBO Rep 16(3):297–311. https://doi.org/10.15252/embr.201439464
Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, Mizushima N (2014) The HOPS complex mediates autophagosome–lysosome fusion through interaction with syntaxin 17. Mol Biol Cell 25(8):1327–1337. https://doi.org/10.1091/mbc.E13-08-0447
Kaushik S, Cuervo AM (2012) Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 22(8):407–417. https://doi.org/10.1016/j.tcb.2012.05.006
Kuo HH, Kakadiya R, Wu YC, Su TL, Lee TC, Lin YW, Yih LH (2016) Derivatives of 6-cinnamamido-quinoline-4-carboxamide impair lysosome function and induce apoptosis. Oncotarget 7(25):38078–38090. https://doi.org/10.18632/oncotarget.9348
Laussmann MA, Passante E, Dussmann H, Rauen JA, Wurstle ML, Delgado ME, Devocelle M, Prehn JH, Rehm M (2011) Proteasome inhibition can induce an autophagy-dependent apical activation of caspase-8. Cell Death Differ 18(10):1584–1597. https://doi.org/10.1038/cdd.2011.27
Lee CH, Hung PF, Lu SC, Chung HL, Chiang SL, Wu CT, Chou WC, Sun CY (2019) MCP-1/MCPIP-1 signaling modulates the effects of IL-1beta in renal cell carcinoma through ER stress-mediated apoptosis. Int J Mol Sci. https://doi.org/10.3390/ijms20236101
Lin Z, Zhang Z, Jiang X, Kou X, Bao Y, Liu H, Sun F, Ling S, Qin N, Jiang L, Yang Y (2017) Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells. Oncotarget 8(11):17833–17848. https://doi.org/10.18632/oncotarget.14868
Lin H, Zhang C, Zhang H, Xia YZ, Zhang CY, Luo J, Yang L, Kong LY (2018) Physakengose G induces apoptosis via EGFR/mTOR signaling and inhibits autophagic flux in human osteosarcoma cells. Phytomedicine 42:190–198. https://doi.org/10.1016/j.phymed.2018.03.046
Liu L, Zhang N, Dou Y, Mao G, Bi C, Pang W, Liu X, Song D, Deng H (2017) Lysosomal dysfunction and autophagy blockade contribute to IMB-6G-induced apoptosis in pancreatic cancer cells. Sci Rep 7:41862. https://doi.org/10.1038/srep41862
Lorincz P, Toth S, Benko P, Lakatos Z, Boda A, Glatz G, Zobel M, Bisi S, Hegedus K, Takats S, Scita G, Juhasz G (2017) Rab2 promotes autophagic and endocytic lysosomal degradation. J Cell Biol 216(7):1937–1947. https://doi.org/10.1083/jcb.201611027
Luan W, Pang Y, Li R, Wei X, Jiao X, Shi J, Yu J, Mao H, Liu P (2019) Akt/mTOR-mediated autophagy confers resistance to BET inhibitor JQ1 In ovarian cancer. Oncotargets Ther 12:8063–8074. https://doi.org/10.2147/OTT.S220267
McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, Coxon FP, Miranda de Stegmann D, Bhogaraju S, Maddi K, Kirchof A, Gatti E, Helfrich MH, Wakatsuki S, Behrends C, Pierre P, Dikic I (2015) PLEKHM1 regulates autophagosome–lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol Cell 57(1):39–54. https://doi.org/10.1016/j.molcel.2014.11.006
Militello RD, Colombo MI (2011) A membrane is born: origin of the autophagosomal compartment. Curr Mol Med 11(3):197–203. https://doi.org/10.2174/156652411795243441
Mittal S, Sharma PK, Tiwari R, Rayavarapu RG, Shankar J, Chauhan LKS, Pandey AK (2017) Impaired lysosomal activity mediated autophagic flux disruption by graphite carbon nanofibers induce apoptosis in human lung epithelial cells through oxidative stress and energetic impairment. Part Fibre Toxicol 14(1):15. https://doi.org/10.1186/s12989-017-0194-4
Mizushima N, Ohsumi Y, Yoshimori T (2002) Autophagosome formation in mammalian cells. Cell Struct Funct 27(6):421–429. https://doi.org/10.1247/csf.27.421
Mizushima N (2007) Autophagy: process and function. Genes Dev 21(22):2861–2873. https://doi.org/10.1101/gad.1599207
Mora R, Régnier-Vigouroux A (2009) Autophagy-driven cell fate decision maker: activated microglia induce specific death of glioma cells by a blockade of basal autophagic flux and secondary apoptosis/necrosis. Autophagy 5(3):419–421. https://doi.org/10.4161/auto.5.3.7881
Moriya S, Che X-F, Komatsu S, Abe A, Kawaguchi T, Gotoh A, Inazu M, Tomoda A, Miyazawa K (2013) Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells. Int J Oncol 42(5):1541–1550. https://doi.org/10.3892/ijo.2013.1870
Nakadera E, Yamashina S, Izumi K, Inami Y, Sato T, Fukushima H, Kon K, Ikejima K, Ueno T, Watanabe S (2016) Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis. Biochem Biophys Res Commun 469(4):1104–1110. https://doi.org/10.1016/j.bbrc.2015.12.010
Nakamura S, Yoshimori T (2017) New insights into autophagosome–lysosome fusion. J Cell Sci 130(7):1209–1216. https://doi.org/10.1242/jcs.196352
Nakashima A, Cheng SB, Kusabiraki T, Motomura K, Aoki A, Ushijima A, Ono Y, Tsuda S, Shima T, Yoshino O, Sago H, Matsumoto K, Sharma S, Saito S (2019) Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts. Sci Rep 9(1):11466. https://doi.org/10.1038/s41598-019-47607-5
Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10(7):458–467. https://doi.org/10.1038/nrm2708
Nazim UM, Jeong JK, Seol JW, Hur J, Eo SK, Lee JH, Park SY (2015) Inhibition of the autophagy flux by gingerol enhances TRAIL-induced tumor cell death. Oncol Rep 33(5):2331–2336. https://doi.org/10.3892/or.2015.3869
Niu Y, Yang X, Chen Y, Jin X, Li L, Guo Y, Li X, Xie Y, Zhang Y, Wang H (2019) EVI1 induces autophagy to promote drug resistance via regulation of ATG7 expression in leukemia cells. Carcinogenesis. https://doi.org/10.1093/carcin/bgz167
Pan J-A, Ullman E, Dou Z, Zong WX (2011) Inhibition of protein degradation induces apoptosis through a microtubule-associated protein 1 light chain 3-mediated activation of caspase-8 at intracellular membranes. Mol Cell Biol 31(15):3158–3170. https://doi.org/10.1128/MCB.05460-11
Pan H, Chen L, Xu Y, Han W, Lou F, Fei W, Liu S, Jing Z, Sui X (2016) Autophagy-associated immune responses and cancer immunotherapy. Oncotarget 7(16):21235–21246. https://doi.org/10.18632/oncotarget.6908
Pan H, Wang Y, Na K, Wang Y, Wang L, Li Z, Guo C, Guo D, Wang X (2019) Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation. Cell Death Dis 10(6):456. https://doi.org/10.1038/s41419-019-1653-7
Park PH (2018) Autophagy induction: a critical event for the modulation of cell death/survival and inflammatory responses by adipokines. Arch Pharmacal Res 41(11):1062–1073. https://doi.org/10.1007/s12272-018-1082-7
Pellerito O, Notaro A, Sabella S, De Blasio A, Vento R, Calvaruso G, Giuliano M (2014) WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation. Apoptosis 19(6):1029–1042. https://doi.org/10.1007/s10495-014-0985-0
Prajapati P, Dalwadi P, Gohel D, Singh K, Sripada L, Bhatelia K, Joshi B, Roy M, Wang WX, Springer JE, Singh R, Singh R (2019) Enforced lysosomal biogenesis rescues erythromycin- and clindamycin-induced mitochondria-mediated cell death in human cells. Mol Cell Biochem 461(1–2):23–36. https://doi.org/10.1007/s11010-019-03585-w
Rasheduzzaman M, Park SY (2018) Antihypertensive drug-candesartan attenuates TRAIL resistance in human lung cancer via AMPK-mediated inhibition of autophagy flux. Exp Cell Res 368(1):126–135. https://doi.org/10.1016/j.yexcr.2018.04.022
Rashid HO, Yadav RK, Kim HR, Chae HJ (2015) ER stress: autophagy induction, inhibition and selection. Autophagy 11(11):1956–1977. https://doi.org/10.1080/15548627.2015.1091141
Raveendran S, Sen A, Ito-Tanaka H, Kato K, Maekawa T, Kumar DS (2019) Advanced microscopic evaluation of parallel type I and type II cell deaths induced by multi-functionalized gold nanocages in breast cancer. Nanoscale Adv 1(3):989–1001
Reggiori F, Ungermann C (2017) Autophagosome maturation and fusion. J Mol Biol 429(4):486–496. https://doi.org/10.1016/j.jmb.2017.01.002
Rossi A, Pakhomova ON, Mollica PA, Casciola M, Mangalanathan U, Pakhomov AG, Muratori C (2019) Nanosecond pulsed electric fields induce endoplasmic reticulum stress accompanied by immunogenic cell death in murine models of lymphoma and colorectal cancer. Cancers (Basel) 11(12):2034. https://doi.org/10.3390/cancers11122034
Rubinsztein DC, Cuervo AM, Ravikumar B, Sarkar S, Korolchuk V, Kaushik S, Klionsky DJ (2009) In search of an “autophagomometer". Autophagy 5(5):585–589. https://doi.org/10.4161/auto.5.5.8823
Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15(7):741–750. https://doi.org/10.1038/ncb2757
Simonsen A, Tooze SA (2009) Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol 186(6):773–782. https://doi.org/10.1083/jcb.200907014
Song X, Liu L, Chang M, Geng X, Wang X, Wang W, Chen TC, Xie L, Song X (2019) NEO212 induces mitochondrial apoptosis and impairs autophagy flux in ovarian cancer. J Exp Clin Cancer Res 38(1):239. https://doi.org/10.1186/s13046-019-1249-1
Takats S, Nagy P, Varga A, Pircs K, Karpati M, Varga K, Kovacs AL, Hegedus K, Juhasz G (2013) Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. J Cell Biol 201(4):531–539. https://doi.org/10.1083/jcb.201211160
Takats S, Pircs K, Nagy P, Varga A, Karpati M, Hegedus K, Kramer H, Kovacs AL, Sass M, Juhasz G (2014) Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila. Mol Biol Cell 25(8):1338–1354. https://doi.org/10.1091/mbc.E13-08-0449
Tian L, Yang Y, Li C, Chen J, Li Z, Li X, Li S, Wu F, Hu Z, Yang Z (2018) The cytotoxicity of coxsackievirus B3 is associated with a blockage of autophagic flux mediated by reduced syntaxin 17 expression. Cell Death Dis 9(2):242. https://doi.org/10.1038/s41419-018-0271-0
Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12(9):831–835. https://doi.org/10.1038/ncb0910-831
Vallecillo-Hernandez J, Barrachina MD, Ortiz-Masia D, Coll S, Esplugues JV, Calatayud S, Hernandez C (2018) Indomethacin disrupts autophagic flux by inducing lysosomal dysfunction in gastric cancer cells and increases their sensitivity to cytotoxic drugs. Sci Rep 8(1):3593. https://doi.org/10.1038/s41598-018-21455-1
Wang F, Tang J, Li P, Si S, Yu H, Yang X, Tao J, Lv Q, Gu M, Yang H, Wang Z (2018) Chloroquine enhances the radiosensitivity of bladder cancer cells by inhibiting autophagy and activating apoptosis. Cell Physiol Biochem 45(1):54–66. https://doi.org/10.1159/000486222
Wang K, Tu Y, Wan JB, Chen M, He C (2019) Synergistic anti-breast cancer effect of pulsatilla saponin D and camptothecin through interrupting autophagic-lysosomal function and promoting p62-mediated ubiquitinated protein aggregation. Carcinogenesis. https://doi.org/10.1093/carcin/bgz140
Wong PM, Puente C, Ganley IG, Jiang X (2013) The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9(2):124–137. https://doi.org/10.4161/auto.23323
Xiong J, Zhu MX (2016) Regulation of lysosomal ion homeostasis by channels and transporters. Sci China Life Sci 59(8):777–791. https://doi.org/10.1007/s11427-016-5090-x
Xu XW, Pan CW, Yang XM, Zhou L, Zheng ZQ, Li DC (2018) SP1 reduces autophagic flux through activating p62 in gastric cancer cells. Mol Med Rep 17(3):4633–4638. https://doi.org/10.3892/mmr.2018.8400
Yan X, Zhou R, Ma Z (2019) Autophagy—cell survival and death. Adv Exp Med Biol. https://doi.org/10.1007/978-981-15-0602-4_29
Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC (2010) Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 70(19):7699–7709. https://doi.org/10.1158/0008-5472.CAN-10-1626
Yang K, Lu Y, Xie F, Zou H, Fan X, Li B, Li W, Zhang W, Mei L, Feng S-S (2016) Cationic liposomes induce cell necrosis through lysosomal dysfunction and late-stage autophagic flux inhibition. Nanomedicine (Lond) 12(23):3117–3137. https://doi.org/10.2217/nnm-2016-0289
Yang KC, Sathiyaseelan P, Ho C, Gorski SM (2018) Evolution of tools and methods for monitoring autophagic flux in mammalian cells. Biochem Soc Trans 46(1):97–110. https://doi.org/10.1042/BST20170102
Yang B, Xue Q, Guo J, Wang X, Zhang Y, Guo K, Li W, Chen S, Xue T, Qi X, Wang J (2019) Autophagy induction by the pathogen receptor NECTIN4 and sustained autophagy contribute to peste des petits ruminants virus infectivity. Autophagy 16(5):842–861. https://doi.org/10.1080/15548627.2019.1643184
Yang W, Jiang C, Xia W, Ju H, Jin S, Liu S, Zhang L, Ren G, Ma H, Ruan M, Hu J (2019) Blocking autophagy flux promotes interferon-alpha-mediated apoptosis in head and neck squamous cell carcinoma. Cancer Lett 451:34–47. https://doi.org/10.1016/j.canlet.2019.02.052
Yi H, Wang K, Du B, He L, Ho H, Qiu M, Zou Y, Li Q, Jin J, Zhan Y, Zhao Z, Liu X (2018) Aleuritolic acid impaired autophagic flux and induced apoptosis in hepatocellular carcinoma HepG2 cells. Molecules. https://doi.org/10.3390/molecules23061338
Young MM, Takahashi Y, Khan O, Park S, Hori T, Yun J, Sharma AK, Amin S, Hu CD, Zhang J, Kester M, Wang HG (2012) Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J Biol Chem 287(15):12455–12468. https://doi.org/10.1074/jbc.M111.309104
Yu I-M, Hughson FM (2010) Tethering factors as organizers of intracellular vesicular traffic. Annu Rev Cell Dev Biol 26:137–156. https://doi.org/10.1146/annurev.cellbio.042308.113327
Yu C, Huang X, Xu Y, Li H, Su J, Zhong J, Kang J, Liu Y, Sun L (2013) Lysosome dysfunction enhances oxidative stress-induced apoptosis through ubiquitinated protein accumulation in HeLa cells. Anat Rec (Hoboken) 296(1):31–39. https://doi.org/10.1002/ar.22612
Yuan Y, Chen Y, Peng T, Li L, Zhu W, Liu F, Liu S, An X, Luo R, Cheng J, Liu J, Lu Y (2019) Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition. Clin Sci (Lond) 133(15):1759–1777. https://doi.org/10.1042/CS20190672
Zhang Y-L, Yao YT, Fang NX, Zhou CH, Gong JS, Li LH (2014) Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats. Acta Pharmacol Sin 35(6):758–769. https://doi.org/10.1038/aps.2014.20
Zhang X, Kumstel S, Jiang K, Meng S, Gong P, Vollmar B, Zechner D (2019) LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer. J Adv Res 20:9–21. https://doi.org/10.1016/j.jare.2019.04.006
Zhao YG, Zhang H (2018) Formation and maturation of autophagosomes in higher eukaryotes: a social network. Curr Opin Cell Biol 53:29–36. https://doi.org/10.1016/j.ceb.2018.04.003
Zhao YG, Zhang H (2019) Autophagosome maturation: an epic journey from the ER to lysosomes. J Cell Biol 218(3):757–770. https://doi.org/10.1083/jcb.201810099
Zhu Z, Zhang P, Li N, Kiang KMY, Cheng SY, Wong VK, Leung GK (2019) Lovastatin enhances cytotoxicity of temozolomide via impairing autophagic flux in glioblastoma cells. Biomed Res Int 2019:2710693. https://doi.org/10.1155/2019/2710693
Zinnah KMA, PARK S-Y (2019) Duloxetine enhances TRAIL-mediated apoptosis via AMPK-mediated inhibition of autophagy flux in lung cancer cells. Anticancer Res 39(12):6621–6633. https://doi.org/10.21873/anticanres.13877
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant Nos. NRF-2016R1A6A1A03011325, NRF-2018R1D1A3B07048623).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tilija Pun, N., Jang, WJ. & Jeong, CH. Role of autophagy in regulation of cancer cell death/apoptosis during anti-cancer therapy: focus on autophagy flux blockade. Arch. Pharm. Res. 43, 475–488 (2020). https://doi.org/10.1007/s12272-020-01239-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-020-01239-w