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Tristetraprolin inhibits mitochondrial function through suppression of ?-Synuclein expression in cancer cells.

ABSTRACT: Mitochondrial dynamics play critical roles in maintaining mitochondrial functions. Here, we report a novel mechanism for regulation of mitochondrial dynamics mediated by tristetraprolin (TTP), an AU-rich element (ARE)-binding protein. Overexpression of TTP resulted in elongated mitochondria, down-regulation of mitochondrial oxidative phosphorylation, reduced membrane potential, cytochrome c release, and increased apoptotic cell death in cancer cells. TTP overexpression inhibited the expression of ?-Synuclein (?-Syn). TTP bound to the ARE within the mRNA 3'-untranslated regions (3'-UTRs) of ?-Syn and enhanced the decay of ?-Syn mRNA. Overexpression of ?-Syn without the 3'-UTR restored TTP-induced defects in mitochondrial morphology, mitochondrial oxidative phosphorylation, membrane potential, and apoptotic cell death. Taken together, our data demonstrate that TTP acts as a regulator of mitochondrial dynamics through enhancing degradation of ?-Syn mRNA in cancer cells. This finding will increase understanding of the molecular basis of mitochondrial dynamics.

SUBMITTER: Vo MT

PROVIDER: S-EPMC5522037 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Tristetraprolin inhibits mitochondrial function through suppression of α-Synuclein expression in cancer cells.

Vo Mai-Tram MT Choi Seong Hee SH Lee Ji-Heon JH Hong Chung Hwan CH Kim Jong Soo JS Lee Unn Hwa UH Chung Hyung-Min HM Lee Byung Ju BJ Park Jeong Woo JW Cho Wha Ja WJ

Oncotarget 20170601 26

Mitochondrial dynamics play critical roles in maintaining mitochondrial functions. Here, we report a novel mechanism for regulation of mitochondrial dynamics mediated by tristetraprolin (TTP), an AU-rich element (ARE)-binding protein. Overexpression of TTP resulted in elongated mitochondria, down-regulation of mitochondrial oxidative phosphorylation, reduced membrane potential, cytochrome c release, and increased apoptotic cell death in cancer cells. TTP overexpression inhibited the expression o ...[more]

PMID: 28410208

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Project description:IntroductionOvarian cancer is one of the most common gynecological cancers worldwide. While, therapies against ovarian cancer have not been completely effective, sinomenine has been proved to have anti-tumor activity in various cancer cells. However, study of its anti-ovarian cancer effect is still rare, and the underlying mechanism has not been elucidated. Therefore, we aim to explore the mechanism of sinomenine anti-ovarian cancer.Materials and methodsThe effect of anti-ovarian cancer HeyA8 cells was analyzed by CCK8 and colony formation assay. The mechanism of sinomenine anti-ovarian cancer was explored via high throughput RNA-seq, and then the target mRNA and protein expression were verified by real-time PCR and Western blot, respectively.ResultsWe found that the proliferation and clone formation ability of ovarian cancer HeyA8 cells were markedly reduced by 1.56 mM sinomenine. The transcriptome analysis showed that 2679 genes were differentially expressed after sinomenine treatment in HeyA8 cells, including 1323 down-regulated genes and 1356 up-regulated genes. Gene ontology and KEGG pathway enrichment indicated that differential expression genes (DEGs) between the groups of sinomenine and DMSO-treated HeyA8 cells were mainly involved in the process of the cell cycle, such as kinetochore organization, chromosome segregation, and DNA replication. Strikingly, the top 18 ranked degree genes in the protein-protein interaction (PPI) network were mainly involved in the process of mitosis, such as sister chromatid segregation, condensed chromosome, and microtubule cytoskeleton organization. Moreover, real-time PCR results showed consistent expression trends of DEGs with transcriptome analysis. The results of Western blot showed the expression level of CDK1, which was the highest degree gene in PPI and the main regulator controlling the process of mitosis, and the levels of phosphorylated P-CDK (Thr161) and P-Histone H3 (Ser10) were decreased after being treated with sinomenine.ConclusionOur results demonstrated that sinomenine inhibited the proliferation of HeyA8 cells through suppressing mitosis by down-regulating the expression and the activity of CDK1. The study may provide a preliminary research basis for the application of sinomenine in anti-ovarian cancer.

Dataset Information

Tristetraprolin inhibits mitochondrial function through suppression of ?-Synuclein expression in cancer cells.

Publications

Tristetraprolin inhibits mitochondrial function through suppression of α-Synuclein expression in cancer cells.

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