Inhibition of peptidyl‑prolyl cis‑trans isomerase B mediates cyclosporin A‑induced apoptosis of islet β cells

Wei,Xiao; Zhu,Dan; Feng,Chenchen; Chen,Guofang; Mao,Xiaodong; Wang,Qifeng; Wang,Jie; Liu,Chao

doi:10.3892/etm.2018.6706

Inhibition of peptidyl‑prolyl cis‑trans isomerase B mediates cyclosporin A‑induced apoptosis of islet β cells

Authors:
- Xiao Wei
- Dan Zhu
- Chenchen Feng
- Guofang Chen
- Xiaodong Mao
- Qifeng Wang
- Jie Wang
- Chao Liu
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Affiliations: Department of Endocrinology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China, Department of Endocrinology, Jiangdu People's Hospital of Yangzhou, Yangzhou, Jiangsu 225200, P.R. China, Central Laboratory, Jiangsu Province Blood Center, Nanjing, Jiangsu 210042, P.R. China
Published online on: September 7, 2018 https://doi.org/10.3892/etm.2018.6706
Pages: 3959-3964
Copyright: © Wei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cyclosporin A (CsA) is widely used as an immunosuppressor in the context of organ transplantation or autoimmune disorders. Recent studies have revealed the detrimental effects of CsA on insulin resistance and pancreatic β cell failure; however, the molecular mechanisms are unknown. The present study sought to confirm the associations between CsA and β cell failure, and to investigate the roles of proinsulin folding and endoplasmic reticulum (ER) stress in CsA‑induced β cell failure. The viability of MIN6 cells treated with CsA was evaluated with MTT assay. Expression levels of insulin, peptidyl‑prolyl cis‑trans isomerase B (PPIB), cleaved caspase‑3, phospho‑protein kinase R (PKR)‑like endoplasmic reticulum kinase (p‑PERK), PKR‑like endoplasmic reticulum kinase (PERK), binding immunoglobulin protein (BIP), and C/EBP homologous protein (CHOP) were detected via reducing western blot assay. Non‑reducing western blot analysis was performed to examine the expression of misfolded proinsulin peptides. The proliferation of MIN6 cells was not inhibited by CsA at concentrations <1 µmol/l. CsA treatment resulted in the decreased expression of insulin and PPIB; however, it also increased the phosphorylation of PERK, and upregulated the expression of PERK, BIP, CHOP and cleaved caspase‑3. The results indicated that CsA could induce pancreatic β cell dysfunction and the potential mechanism underlying this phenomenon may be PPIB‑associated proinsulin misfolding, which in turn induces ER stress in β cells.

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1	Shivaswamy V, Boerner B and Larsen J: Post-transplant diabetes mellitus: Causes, treatment, and impact on outcomes. Endocr Rev. 37:37–61. 2016. View Article : Google Scholar : PubMed/NCBI
2	Wang X, Hu YC, Zhang RY, Jin DX, Jiang Y, Zhang HN and Cong HL: Effect of cyclosporin A intervention on the immunological mechanisms of coronary heart disease and restenosis. Exp Ther Med. 12:3242–3248. 2016. View Article : Google Scholar : PubMed/NCBI
3	Bhat M, Pasini E, Copeland J, Angeli M, Husain S, Kumar D, Renner E, Teterina A, Allard J, Guttman DS and Humar A: Impact of immunosuppression on the metagenomic composition of the intestinal microbiome: A systems biology approach to post-transplant diabetes. Sci Rep. 7:102772017. View Article : Google Scholar : PubMed/NCBI
4	Azzi JR, Sayegh MH and Mallat SG: Calcineurin inhibitors: 40 years later, can't live without. J Immunol. 191:5785–5791. 2013. View Article : Google Scholar : PubMed/NCBI
5	Langsford D and Dwyer K: Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes, and implications for management. World J Diabetes. 6:1132–1151. 2015. View Article : Google Scholar : PubMed/NCBI
6	Montero N and Pascual J: Immunosuppression and Post-transplant Hyperglycemia. Curr Diabetes Rev. 11:144–154. 2015. View Article : Google Scholar : PubMed/NCBI
7	Palepu S and Prasad GV: New-onset diabetes mellitus after kidney transplantation: Current status and future directions. World J Diabetes. 6:445–455. 2015. View Article : Google Scholar : PubMed/NCBI
8	Øzbay LA, Smidt K, Mortensen DM, Carstens J, Jørgensen KA and Rungby J: Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. Br J Pharmacol. 162:136–146. 2011. View Article : Google Scholar : PubMed/NCBI
9	Pereira MJ, Palming J, Rizell M, Aureliano M, Carvalho E, Svensson MK and Eriksson JW: Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell surface in human adipocytes: Increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents. J Clin Endocrinol Metab. 99:E1885–E1894. 2014. View Article : Google Scholar : PubMed/NCBI
10	Bai Y, Wei Y, Wu L, Wei J, Wang X and Bai Y: C/EBP β mediates endoplasmic reticulum stress regulated inflammatory response and extracellular matrix degradation in LPS-stimulated human periodontal ligament cells. Int J Mol Sci. 17:3852016. View Article : Google Scholar : PubMed/NCBI
11	Liu M, Wright J, Guo H, Xiong Y and Arvan P: Proinsulin entry and transit through the endoplasmic reticulum in pancreatic beta cells. Vitam Horm. 95:35–62. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ozawa S, Katsuta H, Suzuki K, Takahashi K, Tanaka T, Sumitani Y, Nishida S, Yoshimoto K and Ishida H: Estimated proinsulin processing activity of prohormone convertase (PC) 1/3 rather than PC2 is decreased in pancreatic β-cells of type 2 diabetic patients. Endocr J. 61:607–614. 2014. View Article : Google Scholar : PubMed/NCBI
13	Zhang X, Yuan Q, Tang W, Gu J, Osei K and Wang J: Substrate-favored lysosomal and proteasomal pathways participate in the normal balance control of insulin precursor maturation and disposal in β-cells. PLoS One. 6:e276472011. View Article : Google Scholar : PubMed/NCBI
14	Kim G, Kim JY and Choi HS: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 as a therapeutic target in hepatocellular carcinoma. Biol Pharm Bull. 38:975–979. 2015. View Article : Google Scholar : PubMed/NCBI
15	Ren LQ, Liu W, Li WB, Liu WJ and Sun L: Peptidylprolyl cis/trans isomerase activity and molecular evolution of vertebrate cyclophilin A. Yi Chuan. 38:736–745. 2016.PubMed/NCBI
16	Humbert MV, Mendoza Almonacid HL, Jackson AC, Hung MC, Bielecka MK, Heckels JE and Christodoulides M: Vaccine potential of bacterial macrophage infectivity potentiator (MIP)-like peptidyl prolyl cis/trans isomerase (PPIase) proteins. Expert Rev Vaccines. 14:1633–1649. 2015. View Article : Google Scholar : PubMed/NCBI
17	Cho KI, Orry A, Park SE and Ferreira PA: Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin. ACS Chem Neurosci. 6:1476–1485. 2015. View Article : Google Scholar : PubMed/NCBI
18	Ernst K, Langer S, Kaiser E, Osseforth C, Michaelis J, Popoff MR, Schwan C, Aktories K, Kahlert V, Malesevic M, et al: Cyclophilin-facilitated membrane translocation as pharmacological target to prevent intoxication of mammalian cells by binary clostridial actin ADP-ribosylated toxins. J Mol Biol. 427:1224–1238. 2015. View Article : Google Scholar : PubMed/NCBI
19	Tafazoli A: Cyclosporine use in hematopoietic stem cell transplantation: Pharmacokinetic approach. Immunotherapy. 7:811–836. 2015. View Article : Google Scholar : PubMed/NCBI
20	Wang Z and Zhang L: Treatment effect of cyclosporine A in patients with painful bladder syndrome/interstitial cystitis: A systematic review. Exp Ther Med. 12:445–450. 2016. View Article : Google Scholar : PubMed/NCBI
21	Wang J and Osei K: Proinsulin maturation disorder is a contributor to the defect of subsequent conversion to insulin in β-cells. Biochem Biophys Res Commun. 411:150–155. 2011. View Article : Google Scholar : PubMed/NCBI
22	Wang J, Chen Y, Yuan Q, Tang W, Zhang X and Osei K: Control of precursor maturation and disposal is an early regulative mechanism in the normal insulin production of pancreatic β-cells. PLoS One. 6:e194462011. View Article : Google Scholar : PubMed/NCBI
23	Yuan Q, Tang W, Zhang X, Hinson JA, Liu C, Osei K and Wang J: Proinsulin atypical maturation and disposal induces extensive defects in mouse Ins2+/Akita β-cells. PLoS One. 7:e350982012. View Article : Google Scholar : PubMed/NCBI
24	Fu Z, Gilbert ER and Liu D: Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 9:25–53. 2013. View Article : Google Scholar : PubMed/NCBI
25	Chan JY, Luzuriaga J, Maxwell EL, West PK, Bensellam M and Laybutt DR: The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK. Mol Cell Endocrinol. 413:189–201. 2015. View Article : Google Scholar : PubMed/NCBI
26	Yu C, Cui S, Zong C, Gao W, Xu T, Gao P, Chen J, Qin D, Guan Q, Liu Y, et al: The orphan nuclear receptor NR4A1 protects pancreatic β-cells from endoplasmic reticulum (ER) stress-mediated apoptosis. J Biol Chem. 290:20687–20699. 2015. View Article : Google Scholar : PubMed/NCBI
27	Kwak HJ, Choi HE, Jang J, Park SK, Bae YA and Cheon HG: Bortezomib attenuates palmitic acid-induced ER stress, inflammation and insulin resistance in myotubes via AMPK dependent mechanism. Cell Signal. 28:788–797. 2016. View Article : Google Scholar : PubMed/NCBI
28	Oh YS, Lee YJ, Kang Y, Han J, Lim OK and Jun HS: Exendin-4 inhibits glucolipotoxic ER stress in pancreatic β cells via regulation of SREBP1c and C/EBPβ transcription factors. J Endocrinol. 216:343–352. 2013. View Article : Google Scholar : PubMed/NCBI
29	Cumaoglu A, Arıcıoglu A and Karasu C: Redox status related activation of endoplasmic reticulum stress and apoptosis caused by 4-hydroxynonenal exposure in INS-1 cells. Toxicol Mech Methods. 24:362–367. 2014. View Article : Google Scholar : PubMed/NCBI
30	Reid DW, Chen Q, Tay AS, Shenolikar S and Nicchitta CV: The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum. Cell. 158:1362–1374. 2014. View Article : Google Scholar : PubMed/NCBI