Autophagy induced by glibenclamide serves as a defense against apoptosis in INS-1 rat insulinoma cells

Abstract

Glibenclamide, a blocker of ATP-sensitive potassium channels, has been found to induce apoptosis in some cell types, including pancreatic beta-cells. Since autophagy plays doubleedged roles in pancreatic beta-cell survival, frequently through cross-talking with apoptosis, we investigated if glibenclamide induced autophagy in INS-1 rat insulinoma cells and the influence of autophagy on apoptosis. Mammalian target of rapamycin (mTOR) is a negative regulator of autophagy. As one of the substrates of mTOR, p70 S6 kinase (p70 S6K) is phosphorylated upon mTOR activation. Our results showed that glibenclamide induced an elevated protein level of the autophagy marker LC3-II, while decreasing phosphorylated p70 S6K, indicative of inhibition on mTOR signaling in INS-1 cells. Furthermore, inhibiting glibenclamide-induced autophagy via knocking down the autophagy essential gene Atg7 decreased cell viability and increased apoptosis in INS-1 cells. Our results indicate that glibenclamide induces autophagy in INS-1 cells, and that autophagy activation is exerting a protective activity against apoptosis.

Share and Cite:

Su, H. , Liu, X. , Su, L. , Zhang, L. , Liu, X. , Ji, H. and Rong, H. (2013) Autophagy induced by glibenclamide serves as a defense against apoptosis in INS-1 rat insulinoma cells. Journal of Diabetes Mellitus, 3, 122-128. doi: 10.4236/jdm.2013.33018.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Chen, Z.F., Li, Y.B., Han, J.Y., Wang, J., Yin, J.J., Li, J.B. and Tian, H. (2010) The double-edged effect of autophagy in pancreatic beta cells and diabetes. Autophagy, 7, 12-16. doi:10.4161/auto.7.1.13607
[2] Shintani, T. and Klionsky, D.J. (2004) Autophagy in health and disease: A double-edged sword. Science, 306, 990-995. doi:10.1126/science.1099993
[3] Gonzalez, C.D., Lee, M.S., Marchetti, P., Pietropaolo, M., Towns, R., Vaccaro, M.I., Watada, H. and Wiley, J.W. (2010) The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy, 7, 2-11. doi:10.4161/auto.7.1.13044
[4] Jung, H.S. and Lee, M.S. (2010) Role of autophagy in diabetes and mitochondria. Annals of the New York Academy of Sciences, 1201, 79-83. doi:10.1111/j.1749-6632.2010.05614.x
[5] Pua, H.H., Guo, J., Komatsu, M. and He, Y.W. (2009) Autophagy is essential for mitochondrial clearance in mature T lymphocytes. The Journal of Immunology, 182, 4046-4055. doi:10.4049/jimmunol.0801143
[6] Ebato, C., Uchida, T., Arakawa, M., Komatsu, M., Ueno, T., Komiya, K., Azuma, K., Hirose, T., Tanaka, K., Kominami, E., et al. (2008) Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metabolism, 8, 325-332. doi:10.1016/j.cmet.2008.08.009
[7] Banerjee, R., Beal, M.F. and Thomas, B. (2010) Autophagy in neurodegenerative disorders: Pathogenic roles and therapeutic implications. Trends in Neurosciences, 33, 541-59. doi:10.1016/j.tins.2010.09.001
[8] Jung, H.S., Chung, K.W., Won Kim, J., Kim, J., Komatsu, M., Tanaka, K., Nguyen, Y.H., Kang, T.M., Yoon, K.H., Kim, J.W., et al. (2008) Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metabolism, 8, 318-324. doi:10.1016/j.cmet.2008.08.013
[9] Masini, M., Bugliani, M., Lupi, R., del Guerra, S., Boggi, U., Filipponi, F., Marselli, L., Masiello, P. and Marchetti, P. (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia, 52, 1083-1086. doi:10.1007/s00125-009-1347-2
[10] Choi, S.E., Lee, S.M., Lee, Y.J., Li, L.J., Lee, S.J., Lee, J.H., Kim, Y., Jun, H.S., Lee, K.W. and Kang, Y. (2009) Protective role of autophagy in palmitate-induced INS-1 beta-cell death. Endocrinology, 150, 126-134. doi:10.1210/en.2008-0483
[11] Meijer, A.J. and Codogno, P. (2007) Macroautophagy: Protector in the diabetes drama? Autophagy, 3, 523-526.
[12] Remedi, M.S. and Nichols, C.G. (2008) Chronic antidiabetic sulfonylureas in vivo: Reversible effects on mouse pancreatic beta-cells. PLOS Medicine, 5, Article ID: e206. doi:10.1371/journal.pmed.0050206
[13] Koren, I., Reem, E. and Kimchi, A. (2010) Autophagy gets a brake: DAP1, a novel mTOR substrate, is activated to suppress the autophagic process. Autophagy, 6, 1179-1180. doi:10.4161/aut o.6.8.13338
[14] Vucicevic, L., Misirkic, M., Kristina, J., Vilimanovich, U., Sudar, E., Isenovic, E., Prica, M., Harhaji-Trajkovic, L., Kravic-Stevovic, T., Vladimir ,B., et al. (2010) Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/ mTOR pathway. Autophagy, 7, 40-50. doi:10.4161/auto.7.1.13883
[15] Zhang, Y. and Ren, J. (2010) Autophagy in ALDH2-elicited cardioprotection against ischemic heart disease: Slayer or savior? Autophagy, 6, 1212-1213. doi:10.4161/auto.6.8.13652
[16] Zhao, Y., Wang, L., Yang, J., Zhang, P., Ma, K., Zhou, J., Liao, W. and Zhu, W.G. (2010) Anti-neoplastic activity of the cytosolic FoxO1 results from autophagic cell death. Autophagy, 6, 988-990. doi:10.4161/auto.6.7.13289
[17] Jung, C.H., Ro, S.H., Cao, J., Otto, N.M. and Kim, D.H. (2010) mTOR regulation of autophagy. FEBS Letters, 584, 1287-1295. doi:10.1016/j.febslet.2010.01.017
[18] Kanazawa, T., Taneike, I., Akaishi, R., Yoshizawa, F., Furuya, N., Fujimura, S. and Kadowaki, M. (20004) Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. The Journal of Biological Chemistry, 279, 8452-8459. doi:10.1074/jbc.M306337200
[19] Daido, S., Yamamoto, A., Fujiwara, K., Sawaya, R., Kondo, S. and Kondo, Y. (2005) Inhibition of the DNA-dependent protein kinase catalytic subunit radiosensitizes malignant glioma cells by inducing autophagy. Cancer Research, 65, 4368-4375. doi:10.1158/0008-5472.CAN-04-4202
[20] Marchetti, P. and Masini, M. (2009) Autophagy and the pancreatic beta-cell in human type 2 diabetes. Autophagy, 5, 1055-1056. doi:10.4161/auto.5.7.9511
[21] Kraft, C., Peter, M. and Hofmann, K. (2010) Selective autophagy: Ubiquitin-mediated recognition and beyond. Nature Cell Biology, 12, 836-841. doi:10.1038/ncb0910-836
[22] Liu, X., Yue, P., Chen, S., Hu, L., Lonial, S., Khuri, F.R. and Sun, S.Y. (2007) The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Research, 67, 4981-4988. doi:10.1158/0008-5472.CAN-06-4274
[23] Mizushima, N., Yoshimori, T. and Levine, B. (2010) Methods in mammalian autophagy research. Cell, 140, 313-326. doi:10.1016/j.cell.2010.01.028
[24] Maedler, K., Carr, R.D., Bosco, D., Zuellig, R.A., Berney, T. and Donath, M.Y. (2005) Sulfonylurea induced betacell apoptosis in cultured human islets. The Journal of Clinical Endocrinology & Metabolism, 90, 501-506. doi:10.1210/jc.2004-0699
[25] Hambrock, A., de Oliveira Franz, C.B., Hiller, S. and Osswald, H. (2006) Glibenclamide-induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform SUR1 but not by expression of SUR2B or the mutant SUR1(M1289T). Journal of Pharmacology and Experimental Therapeutics, 316, 1031-1037. doi:10.1124/jpet.105.097501
[26] Sawada, F., Inoguchi, T., Tsubouchi, H., Sasaki, S., Fujii, M., Maeda, Y., Morinaga, H., Nomura, M., Kobayashi, K. and Takayanagi, R. (2008) Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic beta-cell line, MIN6. Metabolism, 57, 1038-1045. doi:10.1016/j.metabol.2008.01.038
[27] Maiuri, M.C., Zalckvar, E., Kimchi, A. and Kroemer, G. (2007) Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nature Reviews Molecular Cell Biology, 8, 741-752. doi:10.1038/nrm2239
[28] Heneka, M.T., Rodriguez, J.J. and Verkhratsky, A. (2010) Neuroglia in neurodegeneration. Brain Research Reviews, 63, 189-211. doi:10.1016/j.brainresrev.2009.11.004
[29] Lian, J., Karnak, D. and Xu, L. (2010) The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy, 6, 1201-1203. doi:10.4161/auto.6.8.13549
[30] Oh, S., Pirooz, S.D., Ni, D., Zhao, Z. and Liang, C. (2010) Anti-autophagic Bcl-2: Not just an innocent bystander. Autophagy, 7, 56-57.
[31] Djavaheri-Mergny, M., Maiuri, M.C. and Kroemer, G. (2010) Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene, 29, 6508. doi:10.1038/onc.2010.514
[32] Chen, Z.H., Lam, H.C., Jin, Y., Kim, H.P., Cao, J., Lee, S.J., Ifedigbo, E., Parameswaran, H., Ryter, S.W. and Choi, A.M. (2010) Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proceedings of the National Academy of Sciences of the United States of America, 107, 18880-18885. doi:10.1073/pnas.1005574107
[33] Zoncu, R., Efeyan, A. and Sabatini, D.M. (2010) mTOR: From growth signal integration to cancer, diabetes and ageing. Nature Reviews Molecular Cell Biology, 12, 21-35.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.