Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Dual Roles of Autophagy and Their Potential Drugs for Improving Cancer Therapeutics

  • Shin, Dong Wook (College of Biomedical and Health Science, Konkuk University)
  • Received : 2020.09.07
  • Accepted : 2020.09.18
  • Published : 2020.11.01
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Abstract

Autophagy is a major catabolic process that maintains cell metabolism by degrading damaged organelles and other dysfunctional proteins via the lysosome. Abnormal regulation of this process has been known to be involved in the progression of pathophysiological diseases, such as cancer and neurodegenerative disorders. Although the mechanisms for the regulation of autophagic pathways are relatively well known, the precise regulation of this pathway in the treatment of cancer remains largely unknown. It is still complicated whether the regulation of autophagy is beneficial in improving cancer. Many studies have demonstrated that autophagy plays a dual role in cancer by suppressing the growth of tumors or the progression of cancer development, which seems to be dependent on unknown characteristics of various cancer types. This review summarizes the key targets involved in autophagy and malignant transformation. In addition, the opposing tumor-suppressive and oncogenic roles of autophagy in cancer, as well as potential clinical therapeutics utilizing either regulators of autophagy or combinatorial therapeutics with anti-cancer drugs have been discussed.

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References

  1. Altman, J. K. and Platanias, L. C. (2012) A new purpose for an old drug: inhibiting autophagy with clarithromycin. Leuk. Lymphoma 53, 1255-1256. https://doi.org/10.3109/10428194.2012.661857
  2. Amaravadi, R., Kimmelman, A. C. and White, E. (2016) Recent insights into the function of autophagy in cancer. Genes Dev. 30, 1913-1930. https://doi.org/10.1101/gad.287524.116
  3. Ben Sahra, I., Tanti, J. F. and Bost, F. (2010) The combination of metformin and 2-deoxyglucose inhibits autophagy and induces AMPK-dependent apoptosis in prostate cancer cells. Autophagy 6, 670-671. https://doi.org/10.4161/auto.6.5.12434
  4. Bhat, P., Kriel, J., Shubha Priya, B., Basappa, Shivananju, N. S. and Loos, B. (2018) Modulating autophagy in cancer therapy: advancements and challenges for cancer cell death sensitization. Biochem. Pharmacol. 147, 170-182. https://doi.org/10.1016/j.bcp.2017.11.021
  5. Bilanges, B., Posor, Y. and Vanhaesebroeck, B. (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nat. Rev. Mol. Cell Biol. 20, 515-534. https://doi.org/10.1038/s41580-019-0129-z
  6. Brana, I., Ocana, A., Chen, E. X., Razak, A. R., Haines, C., Lee, C., Douglas, S., Wang, L., Siu, L. L., Tannock, I. F. and Bedard, P. L. (2014) A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin. Invest. New Drugs 32, 1269-1277. https://doi.org/10.1007/s10637-014-0159-5
  7. Busca, R., Bertolotto, C., Ortonne, J. P. and Ballotti, R. (1996) Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J. Biol. Chem. 271, 31824-31830. https://doi.org/10.1074/jbc.271.50.31824
  8. Carew, J. S., Medina, E. C., Esquivel, J. A., 2nd, Mahalingam, D., Swords, R., Kelly, K., Zhang, H., Huang, P., Mita, A. C., Mita, M. M., Giles, F. J. and Nawrocki, S. T. (2010) Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J. Cell. Mol. Med. 14, 2448-2459. https://doi.org/10.1111/j.1582-4934.2009.00832.x
  9. Cave, D. D., Desiderio, V., Mosca, L., Ilisso, C. P., Mele, L., Caraglia, M., Cacciapuoti, G. and Porcelli, M. (2018) S-Adenosylmethionine-mediated apoptosis is potentiated by autophagy inhibition induced by chloroquine in human breast cancer cells. J. Cell. Physiol. 233, 1370-1383. https://doi.org/10.1002/jcp.26015
  10. Chang, S. B., Miron, P., Miron, A. and Iglehart, J. D. (2007) Rapamycin inhibits proliferation of estrogen-receptor-positive breast cancer cells. J. Surg. Res. 138, 37-44. https://doi.org/10.1016/j.jss.2006.07.003
  11. Chen, N. and Karantza-Wadsworth, V. (2009) Role and regulation of autophagy in cancer. Biochim. Biophys. Acta 1793, 1516-1523. https://doi.org/10.1016/j.bbamcr.2008.12.013
  12. Chiao, M. T., Cheng, W. Y., Yang, Y. C., Shen, C. C. and Ko, J. L. (2013) Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells. Autophagy 9, 1509-1526. https://doi.org/10.4161/auto.25664
  13. Cicchini, M., Karantza, V. and Xia, B. (2015) Molecular pathways: autophagy in cancer--a matter of timing and context. Clin. Cancer Res. 21, 498-504. https://doi.org/10.1158/1078-0432.CCR-13-2438
  14. Cook, K. L., Warri, A., Soto-Pantoja, D. R., Clarke, P. A., Cruz, M. I., Zwart, A. and Clarke, R. (2014) Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin. Cancer Res. 20, 3222-3232. https://doi.org/10.1158/1078-0432.CCR-13-3227
  15. Crowe, S. E. (2019) Helicobacter pylori Infection. N. Engl. J. Med. 380, 1158-1165. https://doi.org/10.1056/NEJMcp1710945
  16. Dang, C. V. and Kim, J. W. (2018) Convergence of cancer metabolism and immunity: an overview. Biomol. Ther. (Seoul) 26, 4-9. https://doi.org/10.4062/biomolther.2017.194
  17. Danhier, P., Banski, P., Payen, V. L., Grasso, D., Ippolito, L., Sonveaux, P. and Porporato, P. E. (2017) Cancer metabolism in space and time: beyond the Warburg effect. Biochim. Biophys. Acta 1858, 556-572. https://doi.org/10.1016/j.bbabio.2017.02.001
  18. El-Mowafy, A. M. and Alkhalaf, M. (2003) Resveratrol activates adenylyl-cyclase in human breast cancer cells: a novel, estrogen receptor-independent cytostatic mechanism. Carcinogenesis 24, 869-873. https://doi.org/10.1093/carcin/bgg015
  19. Galati, S., Boni, C., Gerra, M. C., Lazzaretti, M. and Buschini, A. (2019) Autophagy: a player in response to oxidative stress and DNA damage. Oxid. Med. Cell. Longev. 2019, 5692958.
  20. Galluzzi, L., Pietrocola, F., Bravo-San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., Kimmelman, A., Kumar, S., Levine, B., Maiuri, M. C., Martin, S. J., Penninger, J., Piacentini, M., Rubinsztein, D. C., Simon, H. U., Simonsen, A., Thorburn, A. M., Velasco, G., Ryan, K. M. and Kroemer, G. (2015) Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856-880. https://doi.org/10.15252/embj.201490784
  21. Gammoh, N., Lam, D., Puente, C., Ganley, I., Marks, P. A. and Jiang, X. (2012) Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc. Natl. Acad. Sci. U.S.A. 109, 6561-6565. https://doi.org/10.1073/pnas.1204429109
  22. Golden, E. B., Cho, H. Y., Hofman, F. M., Louie, S. G., Schonthal, A. H. and Chen, T. C. (2015) Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors. Neurosurg. Focus 38, E12.
  23. Grewe, M., Gansauge, F., Schmid, R. M., Adler, G. and Seufferlein, T. (1999) Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res. 59, 3581-3587.
  24. Guo, J. Y. and White, E. (2016) Autophagy, metabolism, and cancer. Cold Spring Harb. Symp. Quant. Biol. 81, 73-78.
  25. Hare, S. H. and Harvey, A. J. (2017) mTOR function and therapeutic targeting in breast cancer. Am. J. Cancer Res. 7, 383-404.
  26. Hori, Y. S., Hosoda, R., Akiyama, Y., Sebori, R., Wanibuchi, M., Mikami, T., Sugino, T., Suzuki, K., Maruyama, M., Tsukamoto, M., Mikuni, N., Horio, Y. and Kuno, A. (2015) Chloroquine potentiates temozolomide cytotoxicity by inhibiting mitochondrial autophagy in glioma cells. J. Neurooncol. 122, 11-20. https://doi.org/10.1007/s11060-014-1686-9
  27. Hou, H., Zhang, Y., Huang, Y., Yi, Q., Lv, L., Zhang, T., Chen, D., Hao, Q. and Shi, Q. (2012) Inhibitors of phosphatidylinositol 3'-kinases promote mitotic cell death in HeLa cells. PLoS ONE 7, e35665. https://doi.org/10.1371/journal.pone.0035665
  28. Huang, Z. (2000) Small molecule inhibitors of Bcl-2 function: modulators of apoptosis and promising anticancer agents. Curr. Opin. Drug Discov. Devel. 3, 565-574.
  29. Jimenez-Guerrero, R., Gasca, J., Flores, M. L., Perez-Valderrama, B., Tejera-Parrado, C., Medina, R., Tortolero, M., Romero, F., Japon, M. A. and Saez, C. (2018) Obatoclax and paclitaxel synergistically induce apoptosis and overcome paclitaxel resistance in urothelial cancer cells. Cancers (Basel) 10, 490. https://doi.org/10.3390/cancers10120490
  30. Jung, C. H., Seo, M., Otto, N. M. and Kim, D. H. (2011) ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7, 1212-1221. https://doi.org/10.4161/auto.7.10.16660
  31. Jung, D., Khurana, A., Roy, D., Kalogera, E., Bakkum-Gamez, J., Chien, J. and Shridhar, V. (2018) Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer. Sci. Rep. 8, 2487. https://doi.org/10.1038/s41598-018-20531-w
  32. Kang, R., Zeh, H. J., Lotze, M. T. and Tang, D. (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 18, 571-580. https://doi.org/10.1038/cdd.2010.191
  33. Kao, C., Chao, A., Tsai, C. L., Chuang, W. C., Huang, W. P., Chen, G. C., Lin, C. Y., Wang, T. H., Wang, H. S. and Lai, C. H. (2014) Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation. Cell Death Dis. 5, e1510. https://doi.org/10.1038/cddis.2014.468
  34. Kaushik, S. and Cuervo, A. M. (2018) The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 19, 365-381. https://doi.org/10.1038/s41580-018-0001-6
  35. Kimmelman, A. C. and White, E. (2017) Autophagy and tumor metabolism. Cell Metab. 25, 1037-1043. https://doi.org/10.1016/j.cmet.2017.04.004
  36. Kocaturk, N. M., Akkoc, Y., Kig, C., Bayraktar, O., Gozuacik, D. and Kutlu, O. (2019) Autophagy as a molecular target for cancer treatment. Eur. J. Pharm. Sci. 134, 116-137. https://doi.org/10.1016/j.ejps.2019.04.011
  37. Koehler, B. C., Jassowicz, A., Scherr, A. L., Lorenz, S., Radhakrishnan, P., Kautz, N., Elssner, C., Weiss, J., Jaeger, D., Schneider, M. and Schulze-Bergkamen, H. (2015) Pan-Bcl-2 inhibitor obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling. BMC Cancer 15, 919. https://doi.org/10.1186/s12885-015-1929-y
  38. Kuma, A., Komatsu, M. and Mizushima, N. (2017) Autophagy-monitoring and autophagy-deficient mice. Autophagy 13, 1619-1628. https://doi.org/10.1080/15548627.2017.1343770
  39. Lee, I. H., Cao, L., Mostoslavsky, R., Lombard, D. B., Liu, J., Bruns, N. E., Tsokos, M., Alt, F. W. and Finkel, T. (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. U.S.A. 105, 3374-3379. https://doi.org/10.1073/pnas.0712145105
  40. Li, J., Chong, T., Wang, Z., Chen, H., Li, H., Cao, J., Zhang, P. and Li, H. (2014) A novel anticancer effect of resveratrol: reversal of epithelialmesenchymal transition in prostate cancer cells. Mol. Med. Rep. 10, 1717-1724. https://doi.org/10.3892/mmr.2014.2417
  41. Li, J. and Hochstrasser, M. (2020) Microautophagy regulates proteasome homeostasis. Curr. Genet. 66, 683-687. https://doi.org/10.1007/s00294-020-01059-x
  42. Li, L. Q., Xie, W. J., Pan, D., Chen, H. and Zhang, L. (2016) Inhibition of autophagy by bafilomycin A1 promotes chemosensitivity of gastric cancer cells. Tumour Biol. 37, 653-659. https://doi.org/10.1007/s13277-015-3842-z
  43. Li, Y. and Chen, Y. (2019) AMPK and autophagy. Adv. Exp. Med. Biol. 1206, 85-108. https://doi.org/10.1007/978-981-15-0602-4_4
  44. Li, Z., Oh, D. Y., Nakamura, K. and Thiele, C. J. (2011) Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo. Cancer 117, 5412-5422. https://doi.org/10.1002/cncr.26133
  45. Li, Z., Tan, F., Liewehr, D. J., Steinberg, S. M. and Thiele, C. J. (2010) In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J. Natl. Cancer Inst. 102, 758-770. https://doi.org/10.1093/jnci/djq125
  46. Liu, J., Long, S., Wang, H., Liu, N., Zhang, C., Zhang, L. and Zhang, Y. (2019) Blocking AMPK/ULK1-dependent autophagy promoted apoptosis and suppressed colon cancer growth. Cancer Cell Int. 19, 336. https://doi.org/10.1186/s12935-019-1054-0
  47. Liu, L., McKeehan, W. L., Wang, F. and Xie, R. (2012) MAP1S enhances autophagy to suppress tumorigenesis. Autophagy 8, 278-280. https://doi.org/10.4161/auto.8.2.18939
  48. Liu, M., Bamodu, O. A., Huang, W. C., Zucha, M. A., Lin, Y. K., Wu, A. T. H., Huang, C. C., Lee, W. H., Yuan, C. C., Hsiao, M., Deng, L., Tzeng, Y. M. and Yeh, C. T. (2017) 4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway. Toxicol. Appl. Pharm. 325, 48-60. https://doi.org/10.1016/j.taap.2017.04.003
  49. Liu, W., Huang, S., Chen, Z., Wang, H., Wu, H. and Zhang, D. (2014) Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: in vitro and in vivo. Pathol. Res. Pract. 210, 764-769. https://doi.org/10.1016/j.prp.2014.03.008
  50. Lou, Z., Ren, T., Peng, X., Sun, Y., Jiao, G., Lu, Q., Zhang, S., Lu, X. and Guo, W. (2013) Bortezomib induces apoptosis and autophagy in osteosarcoma cells through mitogen-activated protein kinase pathway in vitro. J. Int. Med. Res. 41, 1505-1519. https://doi.org/10.1177/0300060513490618
  51. Mahalingam, D., Mita, M., Sarantopoulos, J., Wood, L., Amaravadi, R. K., Davis, L. E., Mita, A. C., Curiel, T. J., Espitia, C. M., Nawrocki, S. T., Giles, F. J. and Carew, J. S. (2014) Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 10, 1403-1414. https://doi.org/10.4161/auto.29231
  52. Marino, G., Salvador-Montoliu, N., Fueyo, A., Knecht, E., Mizushima, N. and Lopez-Otin, C. (2007) Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282, 18573-18583. https://doi.org/10.1074/jbc.M701194200
  53. Marquez, R. T. and Xu, L. (2012) Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am. J. Cancer Res. 2, 214-221.
  54. Mauthe, M., Orhon, I., Rocchi, C., Zhou, X., Luhr, M., Hijlkema, K. J., Coppes, R. P., Engedal, N., Mari, M. and Reggiori, F. (2018) Chloroquine inhibits autophagic flux by decreasing autophagosomelysosome fusion. Autophagy 14, 1435-1455. https://doi.org/10.1080/15548627.2018.1474314
  55. Mishra, A. K. and Dingli, D. (2019) Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells. Leukemia 33, 2695-2709. https://doi.org/10.1038/s41375-019-0470-4
  56. Mizushima, N. (2007) Autophagy: process and function. Genes Dev. 21, 2861-2873. https://doi.org/10.1101/gad.1599207
  57. Momcilovic, M. and Shackelford, D. B. (2018) Imaging cancer metabolism. Biomol. Ther. (Seoul) 26, 81-92. https://doi.org/10.4062/biomolther.2017.220
  58. Morselli, E., Marino, G., Bennetzen, M. V., Eisenberg, T., Megalou, E., Schroeder, S., Cabrera, S., Benit, P., Rustin, P., Criollo, A., Kepp, O., Galluzzi, L., Shen, S., Malik, S. A., Maiuri, M. C., Horio, Y., Lopez-Otin, C., Andersen, J. S., Tavernarakis, N., Madeo, F. and Kroemer, G. (2011) Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615-629. https://doi.org/10.1083/jcb.201008167
  59. Moscat, J. and Diaz-Meco, M. T. (2009) p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 137, 1001-1004. https://doi.org/10.1016/j.cell.2009.05.023
  60. Mowers, E. E., Sharifi, M. N. and Macleod, K. F. (2017) Autophagy in cancer metastasis. Oncogene 36, 1619-1630. https://doi.org/10.1038/onc.2016.333
  61. Neri, L. M., Cani, A., Martelli, A. M., Simioni, C., Junghanss, C., Tabellini, G., Ricci, F., Tazzari, P. L., Pagliaro, P., McCubrey, J. A. and Capitani, S. (2014) Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia 28, 739-748. https://doi.org/10.1038/leu.2013.226
  62. Park, J. M., Jung, C. H., Seo, M., Otto, N. M., Grunwald, D., Kim, K. H., Moriarity, B., Kim, Y. M., Starker, C., Nho, R. S., Voytas, D. and Kim, D. H. (2016) The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547-564. https://doi.org/10.1080/15548627.2016.1140293
  63. Patel, S., Hurez, V., Nawrocki, S. T., Goros, M., Michalek, J., Sarantopoulos, J., Curiel, T. and Mahalingam, D. (2016) Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. Oncotarget 7, 59087-59097. https://doi.org/10.18632/oncotarget.10824
  64. Periyasamy-Thandavan, S., Jackson, W. H., Samaddar, J. S., Erickson, B., Barrett, J. R., Raney, L., Gopal, E., Ganapathy, V., Hill, W. D., Bhalla, K. N. and Schoenlein, P. V. (2010) Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER+ breast cancer cells. Autophagy 6, 19-35. https://doi.org/10.4161/auto.6.1.10323
  65. Petroni, G., Bagni, G., Iorio, J., Duranti, C., Lottini, T., Stefanini, M., Kragol, G., Becchetti, A. and Arcangeli, A. (2020) Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K. Cell Death Dis. 11, 161. https://doi.org/10.1038/s41419-020-2349-8
  66. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G. and Levine, B. (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809-1820. https://doi.org/10.1172/JCI20039
  67. Racoma, I. O., Meisen, W. H., Wang, Q. E., Kaur, B. and Wani, A. A. (2013) Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS ONE 8, e72882. https://doi.org/10.1371/journal.pone.0072882
  68. Ramakrishnan, S., Nguyen, T. M., Subramanian, I. V. and Kelekar, A. (2007) Autophagy and angiogenesis inhibition. Autophagy 3, 512-515.
  69. Rangwala, R., Leone, R., Chang, Y. C., Fecher, L. A., Schuchter, L. M., Kramer, A., Tan, K. S., Heitjan, D. F., Rodgers, G., Gallagher, M., Piao, S., Troxel, A. B., Evans, T. L., DeMichele, A. M., Nathanson, K. L., O'Dwyer, P. J., Kaiser, J., Pontiggia, L., Davis, L. E. and Amaravadi, R. K. (2014a) Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 10, 1369-1379. https://doi.org/10.4161/auto.29118
  70. Rangwala, R., Chang, Y. C., Hu, J., Algazy, K. M., Evans, T. L., Fecher, L. A., Schuchter, L. M., Torigian, D. A., Panosian, J. T., Troxel, A. B., Tan, K. S., Heitjan, D. F., DeMichele, A. M., Vaughn, D. J., Redlinger, M., Alavi, A., Kaiser, J., Pontiggia, L., Davis, L. E., O'Dwyer, P. J. and Amaravadi, R. K. (2014b) Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 10, 1391-1402. https://doi.org/10.4161/auto.29119
  71. Richardson, P. G., Eng, C., Kolesar, J., Hideshima, T. and Anderson, K. C. (2012) Perifosine, an oral, anti-cancer agent and inhibitor of the Akt pathway: mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity. Expert Opin. Drug Metab. Toxicol. 8, 623-633. https://doi.org/10.1517/17425255.2012.681376
  72. Russell, R. C., Tian, Y., Yuan, H., Park, H. W., Chang, Y. Y., Kim, J., Kim, H., Neufeld, T. P., Dillin, A. and Guan, K. L. (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741-750. https://doi.org/10.1038/ncb2757
  73. Russell, R. C., Yuan, H. X. and Guan, K. L. (2014) Autophagy regulation by nutrient signaling. Cell Res. 24, 42-57. https://doi.org/10.1038/cr.2013.166
  74. Saha, A., Blando, J., Tremmel, L. and DiGiovanni, J. (2015) Effect of metformin, rapamycin, and their combination on growth and progression of prostate tumors in HiMyc mice. Cancer Prev. Res. (Phila.) 8, 597-606. https://doi.org/10.1158/1940-6207.CAPR-15-0014
  75. Sell, S., Nicolini, A., Ferrari, P. and Biava, P. M. (2016) Cancer: a problem of developmental biology; scientific evidence for reprogramming and differentiation therapy. Curr. Drug Targets 17, 1103-1110. https://doi.org/10.2174/1389450116666150907102717
  76. Sesen, J., Dahan, P., Scotland, S. J., Saland, E., Dang, V. T., Lemarie, A., Tyler, B. M., Brem, H., Toulas, C., Cohen-Jonathan Moyal, E., Sarry, J. E. and Skuli, N. (2015) Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS ONE 10, e0123721. https://doi.org/10.1371/journal.pone.0123721
  77. Shukla, S., Patric, I. R., Patil, V., Shwetha, S. D., Hegde, A. S., Chandramouli, B. A., Arivazhagan, A., Santosh, V. and Somasundaram, K. (2014) Methylation silencing of ULK2, an autophagy gene, is essential for astrocyte transformation and tumor growth. J. Biol. Chem. 289, 22306-22318. https://doi.org/10.1074/jbc.M114.567032
  78. Su, Z., Yang, Z., Xu, Y., Chen, Y. and Yu, Q. (2015) Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol. Cancer 14, 48. https://doi.org/10.1186/s12943-015-0321-5
  79. Sun, F. D., Wang, P. C., Shang, J., Zou, S. H. and Du, X. (2018) Ibrutinib presents antitumor activity in skin cancer and induces autophagy. Eur. Rev. Med. Pharmacol. Sci. 22, 561-566.
  80. Takamura, A., Komatsu, M., Hara, T., Sakamoto, A., Kishi, C., Waguri, S., Eishi, Y., Hino, O., Tanaka, K. and Mizushima, N. (2011) Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795-800. https://doi.org/10.1101/gad.2016211
  81. Tamargo-Gomez, I. and Marino, G. (2018) AMPK: regulation of metabolic dynamics in the context of autophagy. Int. J. Mol. Sci. 19, 3812. https://doi.org/10.3390/ijms19123812
  82. Tripathi, R., Ash, D. and Shaha, C. (2014) Beclin-1-p53 interaction is crucial for cell fate determination in embryonal carcinoma cells. J. Cell. Mol. Med. 18, 2275-2286. https://doi.org/10.1111/jcmm.12386
  83. Tsujimoto, Y. and Shimizu, S. (2015) Another way to die: autophagic programmed cell death. Cell Death Differ. 12, 1528-1534. https://doi.org/10.1038/sj.cdd.4401777
  84. Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., Linares, J. F., Reina-Campos, M., Umemura, S., Valasek, M. A., Seki, E., Yamaguchi, K., Koike, K., Itoh, Y., Diaz-Meco, M. T., Moscat, J. and Karin, M. (2016) p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935-948. https://doi.org/10.1016/j.ccell.2016.04.006
  85. Vignot, S., Faivre, S., Aguirre, D. and Raymond, E. (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann. Oncol. 16, 525-537. https://doi.org/10.1093/annonc/mdi113
  86. Vogl, D. T., Stadtmauer, E. A., Tan, K. S., Heitjan, D. F., Davis, L. E., Pontiggia, L., Rangwala, R., Piao, S., Chang, Y. C., Scott, E. C., Paul, T. M., Nichols, C. W., Porter, D. L., Kaplan, J., Mallon, G., Bradner, J. E. and Amaravadi, R. K. (2014) Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 10, 1380-1390. https://doi.org/10.4161/auto.29264
  87. Wan, B., Zang, Y. and Wang, L. (2018) Overexpression of Beclin1 inhibits proliferation and promotes apoptosis of human laryngeal squamous carcinoma cell Hep-2. Onco Targets Ther. 11, 3827-3833. https://doi.org/10.2147/OTT.S148869
  88. Wang, G., Zhou, P., Chen, X., Zhao, L., Tan, J., Yang, Y., Fang, Y. and Zhou, J. (2017) The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis. Cancer Biol. Ther. 18, 584-595. https://doi.org/10.1080/15384047.2017.1345386
  89. Wang, Y., Xu, W., Yan, Z., Zhao, W., Mi, J., Li, J. and Yan, H. (2018) Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J. Exp. Clin. Cancer Res. 37, 63. https://doi.org/10.1186/s13046-018-0731-5
  90. White, E., Mehnert, J. M. and Chan, C. S. (2015) Autophagy, metabolism, and cancer. Clin. Cancer Res. 21, 5037-5046. https://doi.org/10.1158/1078-0432.CCR-15-0490
  91. Xu, H. D. and Qin, Z. H. (2019) Beclin 1, bcl-2 and autophagy. Adv. Exp. Med. Biol. 1206, 109-126. https://doi.org/10.1007/978-981-15-0602-4_5
  92. Yang, L., Wan, J., Xiao, S., Barkhouse, D., Zhu, J., Li, G., Lu, B. and Zhang, Z. (2016) BH3 mimetic ABT-737 sensitizes colorectal cancer cells to ixazomib through MCL-1 downregulation and autophagy inhibition. Am. J. Cancer Res. 6, 1345-1357.
  93. Yang, Y. P., Hu, L. F., Zheng, H. F., Mao, C. J., Hu, W. D., Xiong, K. P., Wang, F. and Liu, C. F. (2013) Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol. Sin. 34, 625-635. https://doi.org/10.1038/aps.2013.5
  94. Yorimitsu, T. and Klionsky, D. J. (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ. 12, 1542-1552. https://doi.org/10.1038/sj.cdd.4401765
  95. Yu, H., Yin, S., Zhou, S., Shao, Y., Sun, J., Pang, X., Han, L., Zhang, Y., Gao, X., Jin, C., Qiu, Y. and Wang, T. (2018) Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers. Cell Death Dis. 9, 702. https://doi.org/10.1038/s41419-018-0660-4
  96. Yuan, N., Song, L., Zhang, S., Lin, W., Cao, Y., Xu, F., Fang, Y., Wang, Z., Zhang, H., Li, X., Wang, Z., Cai, J., Wang, J., Zhang, Y., Mao, X., Zhao, W., Hu, S., Chen, S. and Wang, J. (2015) Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. Haematologica 100, 345-356. https://doi.org/10.3324/haematol.2014.113324
  97. Zaffagnini, G., Savova, A., Danieli, A., Romanov, J., Tremel, S., Ebner, M., Peterbauer, T., Sztacho, M., Trapannone, R., Tarafder, A. K., Sachse, C. and Martens, S. (2018) p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 37, e98308. https://doi.org/10.15252/embj.201798308
  98. Zanotto-Filho, A., Braganhol, E., Klafke, K., Figueiro, F., Terra, S. R., Paludo, F. J., Morrone, M., Bristot, I. J., Battastini, A. M., Forcelini, C. M., Bishop, A. J. R., Gelain, D. P. and Moreira, J. C. F. (2015) Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas. Cancer Lett. 358, 220-231. https://doi.org/10.1016/j.canlet.2014.12.044
  99. Zhang, X., Li, W., Wang, C., Leng, X., Lian, S., Feng, J., Li, J. and Wang, H. (2014) Inhibition of autophagy enhances apoptosis induced by proteasome inhibitor bortezomib in human glioblastoma U87 and U251 cells. Mol. Cell. Biochem. 385, 265-275. https://doi.org/10.1007/s11010-013-1835-z
  100. Zhao, X., Fang, Y., Yang, Y., Qin, Y., Wu, P., Wang, T., Lai, H., Meng, L., Wang, D., Zheng, Z., Lu, X., Zhang, H., Gao, Q., Zhou, J. and Ma, D. (2015) Elaiophylin, a novel autophagy inhibitor, exerts antitumor activity as a single agent in ovarian cancer cells. Autophagy 11, 1849-1863. https://doi.org/10.1080/15548627.2015.1017185
  101. Zhu, K., Dunner, K., Jr. and McConkey, D. J. (2010) Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene 29, 451-462. https://doi.org/10.1038/onc.2009.343

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