Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy.

ABSTRACT: Chemoresistance has long been the bottleneck of ovarian cancer (OC) prognosis. It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC, but the underlying mechanisms remain equivocal. Here, we demonstrate a new mechanism where CRL4^CUL4A/DDB1 manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy. CRL4^CUL4A/DDB1 depletion enhanced mitochondrial fission by upregulating AMPKα^Thr172 and MFF^{Ser172/Ser146} phosphorylation, which in turn recruited DRP1 to mitochondria. CRL4^CUL4A/DDB1 loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitocho

SUBMITTER: Meng Y 

PROVIDER: S-EPMC9731993 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature