Abstract 1029: Receptor-interacting protein kinase 1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Although receptor-interacting protein kinase 1 (RIP1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in response of cells to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIP1 functions as an important pro-survival mechanism in melanoma cells undergoing ER stress through activation of autophagy. While pharmacological induction of ER stress upregulated RIP1 and triggered autophagy in melanoma cells resistant to ER stress-induced apoptosis, knockdown of RIP1 inhibited autophagy and rendered the cells sensitive to killing by ER stress, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIP1 enhanced induction of autophagy and conferred resistance of melanoma cells to killing by ER stress. Activation of JNK, which phosphorylated the BH3-only protein Bim leading to its dissociation from Beclin-1, was involved in ER stress-induced, RIP1-mediated activation of autophagy in melanoma cells. On the other hand, activation of the transcription factor heat shock factor protein 1 (HSF1) downstream of the IRE1/XBP1 axis of the unfolded protein response was responsible for the increase in RIP1 in melanoma cells undergoing ER stress. Collectively, these results identify upregulation of RIP1 as an important adaptive mechanism of melanoma cells to ER stress by protecting against cell death through activation of autophagy, and suggest that targeting the autophagy-activating mechanism of RIP1 may be a useful strategy to enhance sensitivity of melanoma cells to therapeutic agents that induce ER stress. Citation Format: Xu Guang Yan, Qi Luan, Lei Jin, Chen Chen Jiang, Kwang Hong Tay, Fritz Lai, Xiao Ying Liu, Yi Lun Liu, Su Tang Guo, Hsin-Yi Tseng, Xu Dong Zhang. Receptor-interacting protein kinase 1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1029. doi:10.1158/1538-7445.AM2015-1029