Preprint Brief Report Version 1 Preserved in Portico This version is not peer-reviewed

PKCeta Promotes Stress-induced Autophagy and Senescence in Breast Cancer Cells, Presenting A Target for Therapy

Version 1 : Received: 26 June 2022 / Approved: 10 July 2022 / Online: 10 July 2022 (06:42:23 CEST)

A peer-reviewed article of this Preprint also exists.

Rotem-Dai, N.; Muraleedharan, A.; Livneh, E. PKCeta Promotes Stress-Induced Autophagy and Senescence in Breast Cancer Cells, Presenting a Target for Therapy. Pharmaceutics 2022, 14, 1704. Rotem-Dai, N.; Muraleedharan, A.; Livneh, E. PKCeta Promotes Stress-Induced Autophagy and Senescence in Breast Cancer Cells, Presenting a Target for Therapy. Pharmaceutics 2022, 14, 1704.

Journal reference: Pharmaceutics 2022, 14, 1704
DOI: 10.3390/pharmaceutics14081704

Abstract

The emergence of chemoresistance in neoplastic cells is one of the major obstacles in cancer therapy. Autophagy was recently reported as one of the mechanisms that promote chemoresistance in cancer cells by protecting from apoptosis and driving senescence. Thus, understanding the role of autophagy and its underlying signaling pathways is crucial for the development of new therapeutic strategies to overcome chemoresistance. We have previously reported that PKCη is a stress-induced kinase that confers resistance in breast cancer cells against chemotherapy by inducing senescence. Here we show that PKCη promotes autophagy induced by ER and oxidative stress and facilitates the transition from autophagy to senescence. We demonstrate that PKCη knockdown reduces both the autophagic flux and markers of senescence. Additionally, using autophagy inhibitors, such as chloroquine and 3-methyladenine, we show that PKCη and autophagy are required for establishing senescence in MCF-7 in response to oxidative stress. Different drugs used in the clinic are known to induce autophagy and senescence in breast cancer cells. Our study proposes PKCη as a target for therapeutic intervention, acting in synergy with autophagy-inducing drugs, to overcome resistance and enhance cell death in breast cancer.

Keywords

Protein Kinase C; PKCeta; autophagy; senescence; chemoresistance; oxidative stress; ER stress; 3MA; chloroquine

Subject

LIFE SCIENCES, Biochemistry

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