Abstract P6-05-01: Endoplasmic reticulum resident protein transmembrane protein 33 (TMEM33) induces apoptosis via UPR signaling and autophagy in breast cancer cells

Abstract

Abstract Breast cancer is the most common cancer type in women, with expected incidence of around 232,670 new cases in the US alone each year. Endoplasmic reticulum stress (EnR stress) and the related unfolded protein response (UPR) are activated in breast cancer cells to promote cell survival and endocrine resistance. TMEM33 is a novel transmembrane protein that resides in the endoplasmic reticulum (EnR) and has been shown to activate two of the UPR branches (PERK; IRE1α). However, the cellular functions and underlying mechanism of this EnR resident protein remains largely unknown. In this study, we show that overexpression of TMEM33 induces robust cell death in breast cancer cells. TMEM33 overexpression strongly activates the pro-death JNK-p53 pathway, possibly through the activation of IRE1α. We also observe a significant inhibition of the downstream survivin (also called BIRC5), which is known to inhibit cell death by binding to caspases and blocking their activation. We further show that either the blockage of JNK activation with a small molecule inhibitor, or the overexpression of survivin, protects cells against TMEM33-induced apoptosis. In addition, we demonstrate that TMEM33 overexpression induces autophagy in breast cancer cells (changes in LC3 and p62 expression). Inhibition of autophagy with either the autophagy inhibitor chloroquine, or by knockdown of the autophagy gene Atg5, further sensitizes breast cancer cells to TMEM33 overexpression. Conversely, cell death induced by TMEM33 is decreased by overexpression of the autophagy gene Beclin 1. The findings in this study demonstrate that the novel EnR resident protein TMEM33 induces cell death by activating the IRE1α-JNK-p53-survivin pathway in breast cancer cells. Paradoxically, autophagy is also activated by TMEM33 but the prosurvival action is generally not sufficient to block all of the cell death signaling. Citation Format: Rong Hu, Xiyuan Zhang, Leena Hilakivi-Clarke, Usha Kasid, Robert Clarke. Endoplasmic reticulum resident protein transmembrane protein 33 (TMEM33) induces apoptosis via UPR signaling and autophagy in breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-05-01.