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KHDC1A, a novel translational repressor, induces endoplasmic reticulum-dependent apoptosis.

ABSTRACT: RNA binding proteins are characterized as a new family of apoptosis inducers; however, the mechanism by which they induce apoptosis is poorly understood. KHDC1 family members were recently identified as K-homology (KH)-domain containing RNA binding proteins that are unique to eutherian mammals and highly expressed in oocytes. In this study, we report that the expression of KHDC1A induces caspase-3 dependent apoptosis and inhibits mRNA translation, and the translational repression is independent of apoptosis. We demonstrate that both the N-terminus and C-terminus of KHDC1A are required for its pro-apoptotic and translational repression activities. Furthermore, in the C-terminus of KHDC1A, a putative trans-membrane motif (TMM) is critical for these activities. In addition, the ectopically expressed KHDC1A is localized to the endoplasmic reticulum (ER) and changes the morphology of the ER. The inhibition of ER-specific caspase-12 successfully rescues KHDC1A-induced apoptosis, but not Fas-induced apoptosis. Taken together, we conclude that KHDC1A functions as a global translational repressor and induces apoptosis through an ER-dependent signaling pathway.

SUBMITTER: Cai C

PROVIDER: S-EPMC3429326 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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KHDC1A, a novel translational repressor, induces endoplasmic reticulum-dependent apoptosis.

Cai Congli C Liu Jing J Wang Chao C Shen Jinhua J

DNA and cell biology 20120625 9

RNA binding proteins are characterized as a new family of apoptosis inducers; however, the mechanism by which they induce apoptosis is poorly understood. KHDC1 family members were recently identified as K-homology (KH)-domain containing RNA binding proteins that are unique to eutherian mammals and highly expressed in oocytes. In this study, we report that the expression of KHDC1A induces caspase-3 dependent apoptosis and inhibits mRNA translation, and the translational repression is independent ...[more]

PMID: 22731819

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Project description:Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.

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KHDC1A, a novel translational repressor, induces endoplasmic reticulum-dependent apoptosis.

Publications

KHDC1A, a novel translational repressor, induces endoplasmic reticulum-dependent apoptosis.

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