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PPFIA4 Promotes Colon Cancer Cell Proliferation and Migration by Enhancing Tumor Glycolysis.

ABSTRACT: Dysregulated glycolysis is one of the mechanisms employed by cancer cells to facilitate growth and metastasis. Here we aimed to characterize the PPFIA4 gene, as a glycolysis-related oncogene in promoting the proliferation and migration of colon cancer cells. Using bioinformatical tools including The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA), we found that PPFIA4 expression and methylation levels were higher in colon cancer tissues of different stages than in normal tissues. Higher PPFIA4 level was also positively correlated with poorer survival of patients. PPFIA4 upregulation also correlated with poor prognosis and higher clinical stages of colon cancer patients. Colon cancer cell viability, migration and migration were enhanced after PPFIA4 overexpression. EMT markers and glycolysis were upregulated after PPFIA4 overexpression. PPFIA4 expression was found to be positively correlated with PFKFB3 and ENO2 levels, while knockdown of PFKFB3 and ENO2 reduced cell proliferation, migration, invasion and glycolysis. PPFIA4 upregulation is a potential biomarker in colon cancer which promotes proliferation, migration, invasion and glycolysis. The upregulation of PFKFB3/ENO2 signaling by PPFIA4 is a potential mechanism underlying the oncogenic effects of PPFIA4.

SUBMITTER: Huang J

PROVIDER: S-EPMC8173052 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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PPFIA4 Promotes Colon Cancer Cell Proliferation and Migration by Enhancing Tumor Glycolysis.

Huang Jia J Yang Meiling M Liu Zhaoxia Z Li Xiaoqian X Wang Junfeng J Fu Nian N Cao Ting T Yang Xuefeng X

Frontiers in oncology 20210520

Dysregulated glycolysis is one of the mechanisms employed by cancer cells to facilitate growth and metastasis. Here we aimed to characterize the PPFIA4 gene, as a glycolysis-related oncogene in promoting the proliferation and migration of colon cancer cells. Using bioinformatical tools including The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA), we found that PPFIA4 expression and methylation levels were higher in colon cancer tissues of different stages t ...[more]

PMID: 34094943

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Project description:BackgroundThe development of castration-resistant prostate cancer (CRPC) remains a major obstacle in the treatment of prostate cancer (PCa). Dysregulated mitochondrial function has been linked to the initiation and progression of diverse human cancers. Deciphering the novel molecular mechanisms underlying mitochondrial function may provide important insights for developing novel therapeutics for CRPC.MethodsWe investigate the expression of the protein tyrosine phosphatase receptor type F polypeptide interacting protein alpha 4 (PPFIA4) using public datasets and tumor specimens from PCa cases by immunohistochemistry. Gain- and loss-of-function studies are performed in PCa cell lines and mouse models of subcutaneous xenograft to characterize the role of PPFIA4 in CRPC. Gene expression regulation is evaluated by a series of molecular and biochemical experiments in PCa cell lines. The therapeutic effects of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) inhibitor combined enzalutamide are assessed using in vitro functional assays and in vivo mouse models.ResultsWe show that the increase of PPFIA4 exacerbates aggressive phenotype resembling CRPC. A fraction of PPFIA4 localizes to mitochondria and interacts with MTHFD2, a key enzyme for one-carbon metabolism. Androgen deprivation increases the translocation of PPFIA4 into mitochondria and increases the interaction between PPFIA4 and MTHFD2, which result in the elevation of tyrosine phosphorylated MTHFD2. Consequently, the levels of NADPH synthesis increase, resulting in protection against androgen deprivation-induced mitochondrial dysfunction, as well as promotion of tumor growth. Clinically, PPFIA4 expression is significantly increased in CRPC tissues compared with localized PCa ones. Importantly, an MTHFD2 inhibitor, DS18561882, combined with enzalutamide can significantly inhibit CRPC cell proliferation in vitro and tumor growth in vivo.ConclusionOverall, our findings reveal a PPFIA4-MTHFD2 complex in mitochondria that links androgen deprivation to mitochondrial metabolism and mitochondrial dysfunction, which suggest a potential strategy to inhibit CRPC progression.

Dataset Information

PPFIA4 Promotes Colon Cancer Cell Proliferation and Migration by Enhancing Tumor Glycolysis.

Publications

PPFIA4 Promotes Colon Cancer Cell Proliferation and Migration by Enhancing Tumor Glycolysis.

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