biostudies-literatureUnknown30(2)Zheng SUnfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR,Cell death and differentiation327-340https://www.ebi.ac.uk/biostudies/studies/S-EPMC9950372biostudies-literatureiASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers.PMC9950372Liu HLin QHu YZheng SJiang QWang XZhao DLi LfalseiASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers.Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR,2023-01-01T00:00:00Z2023 Feb2025-05-29T21:29:09.64Z2025-05-29T21:29:09.64ZS-EPMC99503723638006410.1038/s41418-022-01086-w