The critical role of GRP78/BiP MARylation in ER stress of KRAS-mutant colorectal cancer
Shuxian Zhang, Xiaodan Chen, Qian Gong, Jing Huang, Yi Tang, Ming Xiao, Ming Li, Qingshu Li, Yalan Wang
TL;DR
This study explores how a specific protein modification helps KRAS-mutant colorectal cancer cells survive and suggests targeting this process could lead to new treatments.
Contribution
The study identifies a novel role for MARylated GRP78/BiP in maintaining ER stability in KRAS-mutant CRC cells.
Findings
KRAS mutations increase ART1, ER stress, and MARylated GRP78/BiP levels in CRC cells.
Inhibiting MARylated GRP78/BiP disrupts ER stress pathways and promotes apoptosis in KRAS-mutant CRC cells.
KRAS-mutant CRC cells are more sensitive to MARylated GRP78/BiP inhibition due to higher ER stability needs.
Abstract
Nearly 50% of patients with KRAS-mutant colorectal cancer (CRC) currently lack effective targeted therapy. The accumulation of KRAS-mutant proteins can trigger a sustained high level of endoplasmic reticulum (ER) stress, and the UPR-based long-term protective regulatory pathway inhibits the aggregation of unfolded proteins, thereby maintaining the stability of the ER and enabling the continued survival of KRAS-mutant tumors. However, the critical factors that affect the regulation of ER homeostasis in KRAS-mutant CRC are still unclear. Mono-ADP ribosylation (MARylation) catalyzed by ART1 is the most important modification of GRP78/BiP and stabilizes the internal environment of the ER. In this study, KRAS mutation increased the levels of ART1, ER stress, and MARylated GRP78/BiP in CRC cells. Inhibiting MARylated GRP78/BiP can impede the downstream IRE1α/XBP1/TFAF2/JNK and PERK/eIF2α/ATF4…
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Taxonomy
TopicsEndoplasmic Reticulum Stress and Disease · Cellular transport and secretion · PARP inhibition in cancer therapy