RSK2 protects human breast cancer cells under endoplasmic reticulum stress through activating AMPKα2-mediated autophagy

Abstract

Autophagy can protect stressed cancer cell by degradation of damaged proteins and organelles. However, the regulatory mechanisms behind this cellular process remain incompletely understood. Here, we demonstrate that RSK2 (p90 ribosomal S6 kinase 2) plays a critical role in ER stress-induced autophagy in breast cancer cells. We demonstrated that the promotive effect of RSK2 on autophagy resulted from directly binding of AMPKα2 in nucleus and phosphorylating it at Thr172 residue. IRE1α, an ER membrane-associated protein mediating unfolded protein response (UPR), is required for transducing the signal for activation of ERK1/2-RSK2 under ER stress. Suppression of autophagy by knockdown of RSK2 enhanced the sensitivity of breast cancer cells to ER stress both in vitro and in vivo. Furthermore, we demonstrated that inhibition of RSK2-mediated autophagy rendered breast cancer cells more sensitive to paclitaxel, a chemotherapeutic agent that induces ER stress-mediated cell death. This study identifies RSK2 as a novel controller of autophagy in tumor cells and suggests that targeting RSK2 can be exploited as an approach to reinforce the efficacy of ER stress-inducing agents against cancer.

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Fig. 1: RSK2 promotes autophagy under ER stress in breast cancer cells.
Fig. 2: AMPKα2 is necessary for RSK2-mediated autophagy in breast cancer cells upon ER stress.
Fig. 3: RSK2 directly associates with AMPKα2 and phosphorylates AMPKα2.
Fig. 4: IRE1α/ERK1/2 contributes to RSK2-mediated autophagy upon ER stress.
Fig. 5: Inhibition of RSK2 decreases proliferation and induces apoptosis in breast cancer cells under ER stress.
Fig. 6: Silencing of RSK2 inhibits xenograft tumor growth in vivo.
Fig. 7: Knockdown of RSK2 decreases autophagy, but increases apoptosis and decreases proliferation in human breast cancer cells subjected to paclitaxel.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China under Grant Nos. 81472593 and 81972480; the Postgraduate Research and Innovation Project of Central South University under Grant No. 1053320183910.

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Correspondence to Yan Cheng.

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Li, L., Chen, X., Wang, K. et al. RSK2 protects human breast cancer cells under endoplasmic reticulum stress through activating AMPKα2-mediated autophagy. Oncogene 39, 6704–6718 (2020). https://doi.org/10.1038/s41388-020-01447-0

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