Abstract
Objectives
To determine the role of endoplasmic reticulum (ER) stress and autophagy in apoptosis induced by bortezomib in human cervical cancer-derived HeLa cells and CaSki cells.
Results
Bortezomib treatment activated apoptosis, evidenced by increased expression of cleaved caspase-3 and cleaved PARP in both HeLa cells and CaSki cells. Bortezomib also induced the loss of the mitochondrial membrane potential, increased the level of ER stress-associated proteins GRP78, ATF4, and CCAAT-enhancer-binding protein homologous protein, and affected the expression of autophagy-related proteins; increasing the levels of LC3-II and ATG5–ATG12 and decreasing the level of p62. When we combined bortezomib with the ER stress activator tunicamycin, or autophagy inhibitors 3-methyladenine or chloroquine, cell growth inhibition and apoptosis were markedly enhanced.
Conclusions
Bortezomib activates apoptosis signaling, and activation of ER stress and inhibition of autophagy enhances the cytotoxicity of bortezomib, suggesting that these combination treatments may be potential chemotherapy strategies for treating cervical cancer.
Similar content being viewed by others
References
Chauhan D, Hideshima T, Anderson KC (2005) Proteasome inhibition in multiple myeloma: therapeutic implication. Annu Rev Pharmacol Toxicol 45:465–476
Crawford LJ, Walker B, Irvine AE (2011) Proteasome inhibitors in cancer therapy. J Cell Commun Signal 5:101–110
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–470
Kiliccioglu I, Konac E, Varol N, Gurocak S, Yucel Bilen C (2014) Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines. Genet Mol Res 13:3721–3731
Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030
Laussmann MA, Passante E, Düssmann H, Rauen JA, Würstle 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 18:1584–1597
Moriya S, Che XF, 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 42:1541–1550
Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885
Wei Q, Dong G, Franklin J, Dong Z (2007) The pathological role of Bax in cisplatin nephrotoxicity. Kidney Int 72:53–62
Zeng H, Zhang S, Yang KY, Wang T, Hu JL, Huang LL, Wu G (2010) Knockdown of second mitochondria-derived activator of caspase expression by RNAi enhances growth and cisplatin resistance of human lung cancer cells. Cancer Biother Radiopharm 25:705–712
Zhong JT, Xu Y, Yi HW, Su J, Yu HM, Xiang XY, Li XN, Zhang ZC, Sun LK (2012) The BH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin 1 interaction in human glioma U251 cells. Cancer Lett 323:180–187
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, Y., Bai, C., Lu, D. et al. Endoplasmic reticulum stress and autophagy participate in apoptosis induced by bortezomib in cervical cancer cells. Biotechnol Lett 38, 357–365 (2016). https://doi.org/10.1007/s10529-015-1968-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-015-1968-0