Death sentence: The tale of a fallen endoplasmic reticulum

International audienceEndoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology

Controlling the unfolded protein response-mediated life and death decisions in cancer

International audienceCancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, leading to activation of stress response pathways. The unfolded protein response (UPR) is the cellular response to endoplasmic reticulum (ER) stress and plays a pivotal role in tumor development. Depending on ER stress intensity and duration, the UPR is either pro-survival to preserve ER homeostasis or pro-death if the stress cannot be resolved. On one hand, the adaptive arm of the UPR is essential for cancer cells to survive the harsh conditions they are facing, and on the other hand, cancer cells have evolved mechanisms to bypass ER stress-induced cell death, thereby conferring them with a selective advantage for malignant transformation. Therefore, the mechanisms involved in the balance between survival and death outcomes of the UPR may be exploited as therapeutic tools to treat cance

Regulated IRE1 alpha-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer

International audienceIRE1 alpha cleaves several mRNAs upon accumulation of misfolded proteins. Here the authors show that active IRE1 alpha cleaves DGAT2 mRNA encoding the rate-limiting enzyme in the synthesis of triacylglycerols, suggesting a role of IRE1 alpha in reprogramming lipid metabolism in cancer cells. IRE1 alpha is constitutively active in several cancers and can contribute to cancer progression. Activated IRE1 alpha cleaves XBP1 mRNA, a key step in production of the transcription factor XBP1s. In addition, IRE1 alpha cleaves select mRNAs through regulated IRE1 alpha-dependent decay (RIDD). Accumulating evidence implicates IRE1 alpha in the regulation of lipid metabolism. However, the roles of XBP1s and RIDD in this process remain ill-defined. In this study, transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1 alpha reveals changes in lipid metabolism genes associated with accumulation of triacylglycerols (TAGs). We identify DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Inhibition of IRE1 alpha, leads to DGAT2-dependent accumulation of TAGs in lipid droplets and sensitizes cells to nutritional stress, which is rescued by treatment with the DGAT2 inhibitor PF-06424439. Our results highlight the importance of IRE1 alpha RIDD activity in reprograming cellular lipid metabolism

Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

IRE1/XBP-1 activation has a major role in Triple negative breast cancer (TNBC). Here, the authors show that inhibition of IRE1’s RNase activity attenuates autocrine and paracrine signaling of pro-tumorigenic cytokines and synergizes with paclitaxel to confer potent anti-tumor effects in TNBC