Dual RNase activity of IRE1 as a target for anticancer therapies

Abstract

The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic. Graphical abstract

Progress of natural sesquiterpenoids in the treatment of hepatocellular carcinoma

“…ER stress could mediate apoptosis by different pathways. Under unfolded protein response (UPR) conditions, Inositol-requiring enzyme 1 (IRE1) can activate XBP-1 mRNA, induce transcription and translation of ER molecular chaperones gene, and alleviate ER stress ( 108 – 110 ). IRE1 can also combine with TRAF2 to increase ER stress through kinase activity and activate ASK and JNK protein kinases in the presence of ASK1 to initiate the apoptotic cascade.…”