MCL1 nuclear translocation induces chemoresistance in colorectal carcinoma

作者：Dechen Fu, Luke Pfannenstiel, Abeba Demelash, Yee Peng Phoon, Cameron Mayell, Claudia Cabrera, Caini Liu, Junjie Zhao, Josephine K. Dermawan, Deepa T. Patil, Jennifer DeVecchio, Matthew F. Kalady, Andrew J. Souers, Darren C. Phillips, Xiaoxia Li, Brian Gastman · 发表于：Cell Death and Disease · 年份：2022 · DOI：10.1038/s41419-021-04334-y · 被引用次数：26 · 研究领域：Cell death mechanisms and regulation、Cancer-related Molecular Pathways、DNA Repair Mechanisms

Abstract Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2 family members is a well-studied means by which this protein confers resistance to multiple anti-cancer therapies. We found that specific DNA damaging chemotherapies promote nuclear MCL1 translocation in CRC models. In p53 null CRC, this process is associated with resistance to chemotherapeutic agents, the mechanism of which is distinct from the classical mitochondrial protection. We previously reported that MCL1 has a noncanonical chemoresistance capability, which requires a novel loop domain that is distinct from the BH3-binding domain associated with anti-apoptotic function. Herein we disclose that upon treatment with specific DNA-damaging chemotherapy, this loop domain binds directly to alpha-enolase which in turn binds to calmodulin; we further show these protein−protein interactions are critical in MCL1’s nuclear import and chemoresistance. We additionally observed that in chemotherapy-treated p53 −/− CRC models, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors, which has significant translational relevance given the co-expression of these proteins in CRC patient samples. Together these findings indicate that chemotherapy-induced MCL1 translocatio...