Inhibition of ERα/ERK/P62 cascades induces “autophagic switch” in the estrogen receptor-positive breast cancer cells exposed to gemcitabine

Abstract

Several clinical trials revealed that estrogen receptor (ER) status had relevance to the response of mammary malignancy to chemotherapy. Autophagy has emerged as an important cellular mechanism of tumor cells in response to anticancer therapy. The aim of this study is to investigate whether gemcitabine induces autophagy, and more importantly, whether such autophagy is functional relevant to the therapeutic effects of gemcitabine in breast cancer cells in relation to the ER status. In our study, autophagy was induced both in ER+ MCF-7 and ER− MDA-MB-231 cells by gemcitabine markedly, while the autophagy plays distinct roles – cytoprotective in ER− MDA-MB-231 and cytotoxic in ER+ MCF-7 cells. Gemcitabine treatment leads to the activation of ERα-ERK-P62 signal pathway in MCF-7 cells which may augment the autophagic degradation, thus results in the excessive activation of autophagy and irreversible autophagic cell death eventually. Inhibition of ERα-ERK-P62 cascades in MCF-7 cells by small interfering RNA or PD98059 impairs the autophagic degradation, and leads to “autophagic switch” – from cytotoxic autophagy to cytoprotection. Moreover, stable overexpression of ERα in the ER− BCap37 breast cancer cell line enhances the gemcitabine-induced autophagy flux and switches the autophagic cytoprotection in ER− BCap37 to cytotoxicity effect in ER+ BCap37 cells. Our study firstly demonstrated that ER status influences gemcitabine efficacy via modulating the autophagy in breast cancer cells.

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

“…Studies have found that phosphorylation of Erk induces autophagy in human cervical cancer Hela cells (31) and liver cancer cells (22). We found that 40 nmol/l TPI could increase p-p38 MAPK and p-Erk expression after treatment for 24 h. Erk activation is closely related to autophagy induction (16,30,32). When combined with Erk inhibitor U0126, as shown in Fig.…”

“…Phosphorylated Erk1/2 can suppress cell growth, and also promotes the expression of Beclin-1 (30). Studies have found that phosphorylation of Erk induces autophagy in human cervical cancer Hela cells (31) and liver cancer cells (22).…”

Differences in the starvation-induced autophagy response in MDA-MB-231 and MCF-7 breast cancer cells

“…Therefore, the differences response to starvation in ATG genes described above likely contribute to the targeted therapy of breast cancer. It has been reported that ER status is relevant to the difference in autophagic response in breast cancer (Shen et al 2016 ), however, whether the specific role of these genes depends on ER status in anti-cancer therapy needs further study.…”

“…Inversely, deregulation of autophagy has been linked to several organismal pathologies including cancer (Levine & Kroemer 2008 ; Mowers et al 2017 ). Recently, it has been shown that autophagy plays a pivotal role in growth, metastasis and invasion of breast cancer (Zhou et al 2016 ), and the function of autophagy is distinct in different breast cancer subtypes, for example, cytoprotection in MDA-MB-231 cells and cytotoxicity in MCF-7 cells has been observed during gemcitabine-induced autophagy (Shen et al 2016 ). Therefore, the adaptive regulation of autophagy could augment the effects of anti-cancer therapy in breast cancer (Rebecca & Amaravadi 2016 ).…”

HMGB1-mediated autophagy attenuates gemcitabine-induced apoptosis in bladder cancer cells involving JNK and ERK activation

“…Autophagy alteration may be another contributing factor [ 18 ]. Gemcitabine can activate autophagy in different types of cancer cells such as that of bladder cancer [ 19 ], breast cancer [ 20 , 21 ] and pancreatic cancer [ 22 , 23 ]. The role of autophagy in a cell's fate is cell or tissue type-specific, and depends on stimuli, activation duration and intensity, and related signaling [ 24 , 25 ].…”