Fol. Biol. 2020, 66, 186-203

https://doi.org/10.14712/fb2020066050186

Exendin-4 Induces Cytotoxic Autophagy in Two Ovarian Cancer Cell Lines through Inhibition of Mtorc1 Mediated by Activation of AMPK and Suppression of Akt

Rehab M. Badi1,2, E. F. Khaleel1,3, M. H. El-Bidawy3,4, H. H. Satti5,6, D. G. Mostafa1,7

1Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
2Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
3Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
4Department of BMS, Division of Physiology, College of Medicine, Prince Sattam Ibn Abdulaziz University, Al-Kharj, Saudi Arabia
5Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
6Department of Pathology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
7Department of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt

Received May 2020
Accepted October 2020

References

1. Arakawa, M., Mita, T., Azuma, K., Ebato, C., Goto, H., Nomiyama, T., Fujitani, Y., Hirose, T., Kawamori, R., Watada, H. (2010) Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59, 1030-1037. <https://doi.org/10.2337/db09-1694>
2. 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, 25520-25532. <https://doi.org/10.18632/oncotarget.4550>
3. Bao, L., Jaramillo, M. C., Zhang, Z., Zheng, Y., Yao, M., Zhang, D. D., Yi, X. (2015) Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells. Mol. Med. Rep. 11, 91-98. <https://doi.org/10.3892/mmr.2014.2671>
4. Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Øvervatn, A., Stenmark, H., Johansen, T. (2005) p62/ SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603-614. <https://doi.org/10.1083/jcb.200507002>
5. 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, 5292-5303. <https://doi.org/10.3390/ijms15045292>
6. Candeias, E., Sebastião, I., Cardoso, S., Carvalho, C., Santos, M. S., Oliveira, C. R., Moreira, P. I., Duarte, A. I. (2018) Brain GLP-1/IGF-1 signaling and autophagy mediate exendin-4 protection against apoptosis in type 2 diabetic rats. Mol. Neurobiol. 55, 4030-4050.
7. Chen, Y. T., Tsai, T. H., Yang, C. C., Sun, C. K., Chang, L. T., Chen, H. H., Chang, C. L., Sung, P. H., Zhen, Y. Y., Leu, S., Chang, H. W., Chen, Y. L., Yip, H. K. (2013) Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J. Transl. Med. 11, 270 <https://doi.org/10.1186/1479-5876-11-270>
8. Correa, R. J. M., Valdes, Y. R., Shepherd, T. G., DiMattia, G. E. (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. <https://doi.org/10.1186/s13048-015-0182-y>
9. Czogalla, B., Kahaly, M., Mayr, D., Schmoeckel, E., Niesler, B., Kolben, T., Burges, A., Mahner, S., Jeschke, U., Trillsch, F. (2019) Interaction of ERα and NRF2 impacts survival in ovarian cancer patients. Int. J. Mol. Sci. 20, 112. <https://doi.org/10.3390/ijms20010112>
10. Ding, Z., Liu, S., Wang, X., Dai, Y., Khaidakov, M., Romeo, F., Mehta, J. L. (2014) LOX-1, oxidant stress, mtDNA damage, autophagy, and immune response in atherosclerosis. Can. J. Physiol. Pharmacol. 92, 524-530 <https://doi.org/10.1139/cjpp-2013-0420>
11. Duran, A., Linares, J. F., Galvez, A. S., Wikenheiser, K., Flores, J. M., Diaz-Meco, M. T., Moscat, J. (2008) The signaling adaptor p62 is an important NF-κB mediator in tumorigenesis. Cancer Cell 13, 343-354. <https://doi.org/10.1016/j.ccr.2008.02.001>
12. Eid, R. A., Bin-Meferij, M. M., El-kott, A. F., Eleawa, S. M., Zaki, M. S. A., Al-Shraim, M., El-Sayed, F., Eldeen, M. A., Alkhateeb, M. A., Alharbi, S. A., Aldera, H., Khalil, M. A. (2020a) Exendin-4 protects against myocardial ischemiareperfusion injury by upregulation of SIRT1 and SIRT3 and activation of AMPK. J. Cardiovasc. Transl. Res. Epub ahead of print. PMID: 32239434. <https://doi.org/10.1007/s12265-020-09984-5>
13. Eid, R. A., Khalil, M. A., Alkhateeb, M. A., Eleawa, S. M., Zaki, M. S. A., El-kott, A. F., Al-Shraim, M., El-Sayed, F., Eldeen, M. A., Bin-Meferij, M. M., Awaji, K. M. E., Shatoor, A. S. (2020b) Exendin-4 attenuates remodeling in the remote myocardium of rats after an acute myocardial infarction by activating β-arrestin-2, protein phosphatase 2A, and glycogen synthase kinase-3 and inhibiting β-catenin. Cardiovasc. Drugs Ther. Epub ahead of print. PMID: 32474680.
14. Ferdaoussi, M., Abdelli, S., Yang, J. Y., Cornu, M., Niederhauser, G., Favre, D., Widmann, C., Regazzi, R., Thorens, B., Waeber, G., Abderrahmani, A. (2008) Exendin-4 protects β-cells from interleukin-1β-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway. Diabetes 57, 1205-1215. <https://doi.org/10.2337/db07-1214>
15. Fidan-Yaylalı, G., Dodurga, Y., Seçme, M., Elmas, L. (2016) Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells. Tumor Biol. 37, 2647-2653. <https://doi.org/10.1007/s13277-015-4104-9>
16. He, W., Yu, S., Wang, L., He, M., Cao, X., Li, Y., Xiao, H. (2016) Exendin-4 inhibits growth and augments apoptosis of ovarian cancer cells. Mol. Cell. Endocrinol. 436, 240-249. <https://doi.org/10.1016/j.mce.2016.07.032>
17. Heppner, K. M., Kirigiti, M., Secher, A., Paulsen, S. J., Buckingham, R., Pyke, C., Knudsen, L. B., Vrang, N., Grove, K. L. (2015) Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology 156, 255-267. <https://doi.org/10.1210/en.2014-1675>
18. Holst, J. J. (2007) The physiology of glucagon-like peptide 1. Physiol. Rev. 87, 1409-1439. <https://doi.org/10.1152/physrev.00034.2006>
19. Inami, Y., Waguri, S., Sakamoto, A., Kouno, T., Nakada, K., Hino, O., Watanabe, S., Ando, J., Iwadate, M., Yamamoto, M., Lee, M. S., Tanaka, K., Komatsu, M. (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 193, 275-284. <https://doi.org/10.1083/jcb.201102031>
20. Iwai, T., Ito, S., Tanimitsu, K., Udagawa, S., Oka, J. I. (2006) Glucagon-like peptide-1 inhibits LPS-induced IL-1β production in cultured rat astrocytes. Neurosci. Res. 55, 352-360. <https://doi.org/10.1016/j.neures.2006.04.008>
21. Iwaya, C., Nomiyama, T., Komatsu, S., Kawanami, T., Tsutsumi, Y., Hamaguchi, Y., Horikawa, T., Yoshinaga, Y., Yamashita, S., Tanaka, T., Terawaki, Y., Tanabe, M., Nabeshima, K., Iwasaki, A., Yanase, T. (2017) Exendin-4, a glucagonlike peptide-1 receptor agonist, attenuates breast cancer growth by inhibiting NF-κB activation. Endocrinology 158, 4218-4232. <https://doi.org/10.1210/en.2017-00461>
22. Khaleel, E. F., Badi, R. M., Satti, H. H., Mostafa, D. G. (2020) Exendin-4 exhibits a tumour suppressor effect in SKOVR-3 and OVACR-3 ovarian cancer cells lines by the activation of SIRT1 and inhibition of NF-κB. Clin. Exp. Pharmacol. Physiol. 47, 1092-1102. <https://doi.org/10.1111/1440-1681.13288>
23. Kim, J. Y., Lim, D. M., Park, H. S., Moon, C. I, Choi, K. J., Lee, S. K., Baik, H. W., Park, K. Y., Kim, B. J. (2012) Exendin- 4 protects against sulfonylurea-induced β-cell apoptosis. J. Pharmacol. Sci. 118, 65-74. <https://doi.org/10.1254/jphs.11072FP>
24. Krause, G. C., Lima, K. G., Levorse, V., Haute, G. V., Gassen, R. B., Garcia, M. C., Pedrazza, L., Donadio, M. V. F., Luft, C., Oliveira, J. R. (2019) Exenatide induces autophagy and prevents the cell regrowth in HEPG2 cells. EXCLI J. 18, 540-548.
25. Lien, E. C., Lyssiotis, C. A., Cantley, L. C. (2016) Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. In: Recent Results in Cancer Research. Springer New York LLC, pp. 39-72.
26. Ligumsky, H., Wolf, I., Israeli, S., Haimsohn, M., Ferber, S., Karasik, A., Kaufman, B., Rubinek, T. (2012) The peptidehormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res. Treat. 132, 449-461. <https://doi.org/10.1007/s10549-011-1585-0>
27. Liu, E. Y., Ryan, K. M. (2012) Autophagy and cancer – issues we need to digest. J. Cell Sci. 125, 2349-2358.
28. Liu, Y., Tong, L., Luo, Y., Li, X., Chen, G., Wang, Y. (2018) Resveratrol inhibits the proliferation and induces the apoptosis in ovarian cancer cells via inhibiting glycolysis and targeting AMPK/mTOR signaling pathway. J. Cell. Biochem. 119, 6162–6172. <https://doi.org/10.1002/jcb.26822>
29. LoPiccolo, J., Blumenthal, G. M., Bernstein, W. B., Dennis, P. A. (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist. Updat. 11, 32-50. <https://doi.org/10.1016/j.drup.2007.11.003>
30. Lu, Z., Yang, H., Sutton, M. N., Yang, M., Clarke, C. H., Liao, W. S. L., Bast, R. C. (2014) ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell Death Differ. 21, 1275-1289. <https://doi.org/10.1038/cdd.2014.48>
31. Luo, Z., Zang, M., Guo, W. (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Futur. Oncol. 6, 457-470. <https://doi.org/10.2217/fon.09.174>
32. Mabuchi, S., Hisamatsu, T., Kimura, T. (2011) Targeting mTOR signaling pathway in ovarian cancer. Curr. Med. Chem. 18, 2960-2968. <https://doi.org/10.2174/092986711796150450>
33. Macciò, A., Madeddu, C. (2012) Inflammation and ovarian cancer. Cytokine 58, 133-1487. <https://doi.org/10.1016/j.cyto.2012.01.015>
34. Manic, G., Obrist, F., Kroemer, G., Vitale, I., Galluzzi, L. (2014) Chloroquine and hydroxychloroquine for cancer therapy. Mol. Cell. Oncol. 1, e29911. <https://doi.org/10.4161/mco.29911>
35. Mariño, G., Niso-Santano, M., Baehrecke, E. H., Kroemer, G. (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 15, 81-94. <https://doi.org/10.1038/nrm3735>
36. Mauthe, M., Orhon, I., Rocchi, C., Zhou, X., Luhr, M., Hijlkema, K. J., Coppes, R. P., Engedal, N., Mari, M., Reggiori, F. (2018) Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 14, 1435-1455. <https://doi.org/10.1080/15548627.2018.1474314>
37. Mizushima, N., Levine, B., Cuervo, A. M., Klionsky, D. J. (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075. <https://doi.org/10.1038/nature06639>
38. Morgan, S. L., Medina, J. E., Taylor, M. M., Dinulescu, D. M. (2014) Targeting platinum resistant disease in ovarian cancer. Curr. Med. Chem. 21, 3009-3020. <https://doi.org/10.2174/0929867321666140414102701>
39. Nomiyama, T., Kawanami, T., Irie, S., Hamaguchi, Y., Terawaki, Y., Murase, K., Tsutsumi, Y., Nagaishi, R., Tanabe, M., Morinaga, H., Tanaka, T., Mizoguchi, M., Nabeshima, K., Tanaka, M., Yanase, T. (2014) Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes 63, 3891-3905. <https://doi.org/10.2337/db13-1169>
40. Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J. A., Outzen, H., Øvervatn, A., Bjørkøy, G., Johansen, T. (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131-24145. <https://doi.org/10.1074/jbc.M702824200>
41. Park, C. W., Kim, H. W., Ko, S. H., Lim, J. H., Ryu, G. R., Chung, H. W., Han, S. W., Shin, S. J., Bang, B. K., Breyer, M. D., Chang, Y. S. (2007) Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J. Am. Soc. Nephrol. 18, 1227-1238. <https://doi.org/10.1681/ASN.2006070778>
42. Peracchio, C., Alabiso, O., Valente, G., Isidoro, C. (2012) Involvement of autophagy in ovarian cancer: a working hypothesis. J. Ovarian Res. 5, 22. <https://doi.org/10.1186/1757-2215-5-22>
43. Pyke, C., Heller, R. S., Kirk, R. K., Ørskov, C., Reedtz-Runge, S., Kaastrup, P., Hvelplund, A., Bardram, L., Calatayud, D., Knudsen, L. B. (2014) GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155, 1280-1290. <https://doi.org/10.1210/en.2013-1934>
44. Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M., Garcia- Arencibia, M., Green-Thompson, Z. W., Jimenez-Sanchez, M., Korolchuk, V. I., Lichtenberg, M., Luo, S., Massey, D. C. O., Menzies, F. M., Moreau, K., Narayanan, U., Renna, M., Siddiqi, F. H., Underwood, B. R., Winslow, A. R., Rubinsztein, D. C. (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383-1435. <https://doi.org/10.1152/physrev.00030.2009>
45. Romaní-Pérez, M., Outeiriño-Iglesias, V., Gil-Lozano, M., González-Matías, L. C., Mallo, F., Vigo, E. (2013) Pulmonary GLP-1 receptor increases at birth and exogenous GLP-1 receptor agonists augmented surfactant-protein levels in litters from normal and nitrofen-treated pregnant rats. Endocrinology 154, 1144-1155. <https://doi.org/10.1210/en.2012-1786>
46. Sharma, S., Mells, J. E., Fu, P. P., Saxena, N. K., Anania, F. A. (2011) GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 6, e25269. <https://doi.org/10.1371/journal.pone.0025269>
47. Shen, Y., Li, D. D., Wang, L. L., Deng, R., Zhu, X. F. (2008) Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy 4, 1067-1068. <https://doi.org/10.4161/auto.6827>
48. Shuvayeva, G., Bobak, Y., Igumentseva, N., Titone, R., Morani, F., Stasyk, O., Isidoro, C. (2014) Single amino acid arginine deprivation triggers prosurvival autophagic response in ovarian carcinoma SKOV3. Biomed Res. Int. 2014, 505041 <https://doi.org/10.1155/2014/505041>
49. Sun, Y., Liu, J. H., Jin, L., Sui, Y. X., Han, L. L., Huang, Y. (2015) Effect of autophagy-related beclin1 on sensitivity of cisplatin-resistant ovarian cancer cells to chemotherapeutic agents. Asian Pacific J. Cancer Prev. 16, 2785-2791. <https://doi.org/10.7314/APJCP.2015.16.7.2785>
50. Tan, W. X., Xu, T. M., Zhou, Z. L., Lv, X. J., Liu, J., Zhang, W. J., Cui, M. H. (2019) TRP14 promotes resistance to cisplatin by inducing autophagy in ovarian cancer. Oncol. Rep. 42, 1343-1354.
51. Tang, J., Zhu, J., Ye, Y., Liu, Y., He, Y., Zhang, L., Tang, D., Qiao, C., Feng, X., Li, J., Kan, Y., Li, X., Jin, X., Kong, D. (2019) Inhibition LC3B can increase chemosensitivity of ovarian cancer cells. Cancer Cell Int. 19, 199. <https://doi.org/10.1186/s12935-019-0921-z>
52. Tian, T., Li, X., Zhang, J. (2019) mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int. J. Mol. Sci. 20, 755. <https://doi.org/10.3390/ijms20030755>
53. Tsutsumi, Y., Nomiyama, T., Kawanami, T., Hamaguchi, Y., Terawaki, Y., Tanaka, T., Murase, K., Motonaga, R., Tanabe, M., Yanase, T., Culig, Z. (2015) Combined treatment with exendin-4 and metformin attenuates prostate cancer growth. PLoS One 10, e0139709 <https://doi.org/10.1371/journal.pone.0139709>
54. Van der Wijst, M. G. P., Brown, R., Rots, M. G. (2014) Nrf2, the master redox switch: the Achilles’ heel of ovarian cancer? Biochim. Biophys. Acta Rev. Cancer 1846, 494-509. <https://doi.org/10.1016/j.bbcan.2014.09.004>
55. Vangoitsenhoven, R., Mathieu, C., Van Der Schueren, B. (2012) GLP1 and cancer: friend or foe? Endocr. Relat. Cancer 19, F77-F88. <https://doi.org/10.1530/ERC-12-0111>
56. Vaughan, S., Coward, J. I., Bast, R. C., Berchuck, A., Berek, J. S., Brenton, J. D., Coukos, G., Crum, C. C., Drapkin, R., Etemadmoghadam, D., Friedlander, M., Gabra, H., Kaye, S. B., Lord, C. J., Lengyel, E., Levine, D. A., McNeish, I. A., Menon, U., Mills, G. B., Nephew, K. P., Oza, A. M., Sood, A. K., Stronach, E. A., Walczak, H., Bowtell, D. D., Balkwill, F. R. (2011) Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. Cancer 11, 719-725. <https://doi.org/10.1038/nrc3144>
57. Vijayakumar, K., Cho, G. (2019) Autophagy: an evolutionarily conserved process in the maintenance of stem cells and aging. Cell Biochem. Funct. 37, 452-458. <https://doi.org/10.1002/cbf.3427>
58. Wei, Q., Sun, Y. Q., Zhang, J. (2012) Exendin-4, a glucagonlike peptide-1 receptor agonist, inhibits cell apoptosis induced by lipotoxicity in pancreatic β-cell line. Peptides 37, 18-24. <https://doi.org/10.1016/j.peptides.2012.06.018>
59. Wei, Y., Han, T., Wang, R., Wei, J., Peng, K., Lin, Q., Shao, G. (2018) LSD1 negatively regulates autophagy through the mTOR signaling pathway in ovarian cancer cells. Oncol. Rep. 40, 425-433.
60. Wu, Y., Deng, J., Rychahou, P. G., Qiu, S., Evers, B. M., Zhou, B. P. (2009) Stabilization of Snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416-428. <https://doi.org/10.1016/j.ccr.2009.03.016>
61. Xia, Y., Shen, S., Verma, I. M. (2014) NF-κB, an active player in human cancers. Cancer Immunol. Res. 2, 823-830. <https://doi.org/10.1158/2326-6066.CIR-14-0112>
62. Xu, Y., Pang, X., Dong, M., Wen, F., Zhang, Y. (2013) Ghrelin inhibits ovarian epithelial carcinoma cell proliferation in vitro. Oncol. Rep. 30, 2063-2070. <https://doi.org/10.3892/or.2013.2692>
63. Yap, M. K. K., Misuan, N. (2019) Exendin-4 from Heloderma suspectum venom: from discovery to its latest application as type II diabetes combatant. Basic Clin. Pharmacol. Toxicol. 124, 513-527. <https://doi.org/10.1111/bcpt.13169>
64. Ylä-Anttila, P., Vihinen, H., Jokitalo, E., Eskelinen, E.-L. (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5, 1180-1185. <https://doi.org/10.4161/auto.5.8.10274>
65. Yun, C. W., Lee, S. H. (2018) The roles of autophagy in cancer. Int. J. Mol. Sci. 19, 3466. <https://doi.org/10.3390/ijms19113466>
66. Yung, M. M. H., Ngan, H. Y. S., Chan, D. W. (2016) Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges. Acta Biochim. Biophys. Sin. (Shanghai) 48, 301-317. <https://doi.org/10.1093/abbs/gmv128>
67. Zhan, L., Yang, Y., Ma, T. T., Huang, C., Meng, X. M., Zhang, L., Li, J. (2015) Transient receptor potential vanilloid 4 inhibits rat HSC-T6 apoptosis through induction of autophagy. Mol. Cell. Biochem. 402, 9-22. <https://doi.org/10.1007/s11010-014-2298-6>
68. 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, 83476-83487. <https://doi.org/10.18632/oncotarget.13080>
69. Zhang, Y., Xu, F., Liang, H., Cai, M., Wen, X., Li, X., Weng, J. (2016) Exenatide inhibits the growth of endometrial cancer Ishikawa xenografts in nude mice. Oncol. Rep. 35, 1340-1348. <https://doi.org/10.3892/or.2015.4476>
70. Zhou, H., Yang, J., Xin, T., Li, D., Guo, J., Hu, S., Zhou, S., Zhang, T., Zhang, Y., Han, T., Chen, Y. (2014) Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/ Akt-Sfrp2 pathways. Free Radic. Biol. Med. 77, 363-375. <https://doi.org/10.1016/j.freeradbiomed.2014.09.033>
71. Zi, D., Zhou, Z. W., Yang, Y. J., Huang, L., Zhou, Z. L., He, S. M., He, Z. X., Zhou, S. F. (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, 27228-27251. <https://doi.org/10.3390/ijms161126018>
72. Zoncu, R., Efeyan, A., Sabatini, D. M. (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21-35. <https://doi.org/10.1038/nrm3025>
73. Zummo, F. P., Cullen, K. S., Honkanen-Scott, M., Shaw, J. A. M., Lovat, P. E., Arden, A. C. (2017) Glucagon-like peptide 1 protects pancreatic β-cells from death by increasing autophagic flux and restoring lysosomal function. Diabetes 66, 1272-1285. <https://doi.org/10.2337/db16-1009>
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