title: Connecting endoplasmic reticulum stress to autophagy through IRE1/JNK/beclin-1 in breast cancer cells.
abstract: Current experimental results indicate that endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which rebuilds ER homeostasis, through which tumor cells can become resistant chemotherapeutic agents. Autophagy is a form of programmed cell death, but it can also play a cytoprotective role in tumor cells, indicating that it has an inverse function. The aim of the present study was to investigate whether tunicamycin (TM) induces autophagy, as well as whether the inhibition of autophagy enhances the apoptosis ofbreast cancer cells induced by TM. In addition, we wished to investigate the mechanisms through which specific UPR targets control autophagy. We found that MCF-7 and MDA-MB‑231 breast cancer cells were insensitive to TM at a relatively low concentration. As shown by western blot analysis, treatment with TM increased the expression of 78 kDa glucose-regulated protein (GRP78), inositol requiring enzyme 1 (IRE1), beclin-1, IRE1α, p-JNK and microtubule-associated protein 1 light chain 3 (LC3); the expression of p62 increased at an early time point during treatment and subsequently decreased. We also used the specific inhibitor of autophagy, 3-methyladenine (3-MA), to elucidate the role of autophagy in ER stress in the breast cancer cells treated with TM. The transformation of LC3-I to LC3-II which was induced by TM, was reversed following treatment with 3-MA. The inhibition of autophagy by 3-MA treatment enhanced the inhibitory and apoptotic rates of TM in the breast cancer cells, as shown by confocal microscopy and flow cytometry. TM increased the misfolded proteins that lead to the activation of ER stress-mediated protection and induced apoptosis paralleled by autophagy in breast cancer cells which was regulated by IRE1/JNK/beclin-1. Autophagy attenuates ER stress by clearing ubiquitinated proteins and decreasing apoptosis, which plays a protective role. The inhibition of autophagy or the promotion of ER stress may be used as therapeutic targets to improve the efficacy of chemotherapeutic drugs.
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Xiu
authors: X
authors: Cheng
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Hao
authors: H
authors: Liu
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Chen-Chen
authors: CC
authors: Jiang
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Lin
authors: L
authors: Fang
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Chao
authors: C
authors: Chen
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Xu-Dong
authors: XD
authors: Zhang
authors: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.
authors: Zhi-Wen
authors: ZW
authors: Jiang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014415:Tunicamycin; C025946:3-methyladenine; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; D000225:Adenine