Interference with mitochondrial metabolism could serve as a potential therapeutic strategy for advanced prostate cancer

Abstract

Metabolic reprogramming has been defined as a hallmark of malignancies. Prior studies have focused on the single nucleotide polymorphism (SNP) of POLG2 gene, which is reportedly responsible for encoding mitochondrial DNA genes and is implicated in the material and energy metabolism of tumor cells, whereas its function in prostate cancer has been elusive. Gene expression profile matrix and clinical information were downloaded from TCGA (The Cancer Genome Atlas) data portal, and GSE3325 and GSE8511 were retrieved from GEO (Gene Expression Omnibus) database. We conducted analysis of the relative expression of POLG2, clinical characterization, survival analysis, GO / KEGG and GSEA (Gene Set Enrichment Analysis) enrichment analysis in R and employed STRING portal to acquaint ourselves with the protein-protein interaction (PPI). IHC (Immunohistochemical) profiles of POLG2 protein between normal and cancerous tissues were consulted via HPA (Human protein atlas) database and the immunohistochemical POLG2 were verified between para-cancerous and cancerous tissues in tissue array. At the cellular level, Mitochondrial dysfunction assay, DNA synthesis test, wound healing assay, and invasion assay were implemented to further validate the phenotype of POLG2 knockdown in PCa cell lines. RT-qPCR and western blotting were routinely adopted to verify variations of molecular expression within epithelial mesenchymal transition (EMT). Results showed that POLG2 was over-expressed in most cancer types, and the over-expression of POLG2 was correlated with PCa progression and suggested poor OS (Overall Survival) and PFI (Progress Free Interval). Multivariate analysis showed that POLG2 might be an independent prognostic factor of prostate cancer. We also performed GO/KEGG, GSEA analysis, co-expression genes, and PPI, and observed the metabolism-related gene alterations in PCa. Furthermore, we verified that POLG2 knockdown had an inhibitory effect on mitochondrial function, proliferation, cell motility, and invasion, we affirmed POLG2 could affect the prognosis of advanced prostate cancer via EMT. In summary, our findings indicate that over-expressed POLG2 renders poor prognosis in advanced prostate cancer. This disadvantageous factor can serve as a potential indicator, making it possible to target mitochondrial metabolism to treat advanced prostate cancer.