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PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway.

ABSTRACT: Human pituitary tumor-transforming gene (PTTG) is a proto-oncogene involved in the development, invasion, and metastasis of many types of cancer, including ovarian cancer. However, little is known about the role of PTTG in the metabolic shift of ovarian cancer cells. In our study, we show that PTTG expression was positively correlated with the differentiation degree of ovarian cancer tissue. In addition, PTTG suppression by specific shRNA could inhibit the proliferation of ovarian cancer cells A2780 and SKOV-3. Furthermore, aerobic glycolysis was suppressed and oxidative phosphorylation was increased in ovarian cancer cells after PTTG suppression. We further found that the expression of c-myc and several crucial enzymes involved in aerobic glycolysis (e.g., PKM2, LDHA, and glucose transporter 1 (GLUT-1)) were downregulated by PTTG knockwown. Overexpression of c-myc could prevent the metabolic shift induced by PTTG knockwown. Together, our findings suggest that the oncogene PTTG promotes the progression of ovarian cancer cells, and its loss resists tumor development, in part, by regulating cellular metabolic reprogramming that supports cell growth and proliferation via c-myc pathway.

SUBMITTER: Wang X

PROVIDER: S-EPMC4747382 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway.

Wang Xiu X Duan Wanxing W Li Xuqi X Liu Jiangbo J Li Donghong D Ye Lianhong L Qian Lu L Yang Aijun A Xu Qinhong Q Liu Han H Fu Qiaoshan Q Wu Erxi E Ma Qingyong Q Shen Xin X

Oncotarget 20151201 38

Human pituitary tumor-transforming gene (PTTG) is a proto-oncogene involved in the development, invasion, and metastasis of many types of cancer, including ovarian cancer. However, little is known about the role of PTTG in the metabolic shift of ovarian cancer cells. In our study, we show that PTTG expression was positively correlated with the differentiation degree of ovarian cancer tissue. In addition, PTTG suppression by specific shRNA could inhibit the proliferation of ovarian cancer cells A ...[more]

PMID: 26516926

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Project description:BackgroundRecently, we have reported the characterization of a novel protein named Coiled-coil Helix Tumor and Metabolism 1 (CHTM1). CHTM1 localizes to both cytosol and mitochondria. Sequence corresponding to CHTM1 is also annotated in the database as CHCHD5. CHTM1 is deregulated in human breast and colon cancers and its deficiency in human cancer cells leads to defective lipid metabolism and poor growth under glucose/glutamine starvation.MethodsHuman cancer cell lines and tissue specimens were used. CHTM1 knockdown was done via lentiviral approach. CHTM1-expresssion constructs were developed and mutants were generated via site-directed mutagenesis approach. Western blotting, immunostaining, immunohistochemistry, cell fractionation and luciferase assays were performed. Reactive oxygen species and reactive nitrogen species were also measured.ResultsHere we report that CHTM1 deficiency sensitizes human lung cancer cells to metabolic stress-induced cell death mediated by glucose/glutamine deprivation and metformin treatment. CHTM1 interacts with Apoptosis Inducing Factor 1 (AIF1) that is one of the important death inducing molecules. CHTM1 appears to negatively regulate AIF1 by preventing AIF1 translocation to cytosol/nucleus and thereby inhibit AIF1-mediated caspase-independent cell death. Our results also indicate that p38, a stress kinase, plays a critical role in metabolic stress-induced cell death in CHTM1-deficient cells. Furthermore, p38 appears to enhance AIF1 translocation from mitochondria to cytosol particularly in metabolically stressed CHTM1-deficient cells and CHTM1 negatively regulates p38 kinase activity. The expression status of CHTM1 in lung cancer patient samples is also investigated and our results indicate that CHTM1 levels are increased in the majority of lung tumors when compared to their matching normal tissues.ConclusionThus, CHTM1 appears to be an important metabolic marker that regulates cancer cell survival under metabolic stress conditions, and has the potential to be developed as a predictive tumor marker.

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PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway.

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PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway.

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