Connecting endoplasmic reticulum stress to autophagy through IRE1/JNK/beclin-1 in breast cancer cells
Authors: Hao Liu
Xiu Cheng
Lin Fang
Xu-Dong Zhang
Chao Chen
Chen-Chen Jiang
Zhi-Wen Jiang
Journal: International Journal of Molecular Medicine (2014)
Discipline: CLINICAL MEDICINE
Keywords: Endoplasmic reticulum stress; Unfolded protein response; Autophagy; Tunicamycin; Breast cancer cells
Affiliations: Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui 233030, P.R. China.

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. 

Retracted: Yes

PubPeer comments:
 Figure 4B contains a set of image duplication after rotation adjustment. ![file] , 
 Figure 4C contains a set of image duplication with different cell cycle ratio. ![file] , 
 Multiple image overlap and duplication in Figure 4E. ![file] , 
 Figure 5B and Figure 6A contain two set of WB band duplication. ![file] , 
 Retracted [5 July 2021] . ------------------------------ Following the publication of this paper, it was drawn to the Editors attention by a concerned reader that possible anomalies were associated with data shown in Fig. 4B, C and E, and western blotting data shown in Fig. 5, such that it was difficult to interpret the presented results as having originated from discrete experiments performed in two breast cancer cell lines (MCFu20117 and MDAu2011MBu2011231). After having investigated the matter internally, the Editor of *International Journal of Molecular Medicine* has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory response. The Editor apologizes to the readership for any inconvenience caused. ,