Abstract
Cells generate adenosine-5′-triphosphate (ATP), the major currency for energy-consuming reactions, through mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. One of the remarkable features of cancer cells is aerobic glycolysis, also known as the “Warburg Effect”, in which cancer cells rely preferentially on glycolysis instead of mitochondrial OXPHOS as the main energy source even in the presence of high oxygen tension. One of the main players in controlling OXPHOS is the mitochondrial gatekeeperpyruvate dehydrogenase complex (PDHc) and its major subunit is E1α (PDHA1). To further analyze the function of PDHA1 in cancer cells, it was knock out (KO) in the human prostate cancer cell line LnCap and a stable KO cell line was established. We demonstrated that PDHA1 gene KO significantly decreased mitochondrial OXPHOS and promoted anaerobic glycolysis, accompanied with higher stemness phenotype including resistance to chemotherapy, enhanced migration ability and increased expression of cancer stem cell markers. We also examined PDHA1 protein expression in prostate cancer tissues by immunohistochemistry and observed that reduced PDHA1 protein expression in clinical prostate carcinomas was significantly correlated with poor prognosis. Collectively, our results show that negative PDHA1 gene expressionis associated with significantly higher cell stemness in prostate cancer cells and reduced protein expression of this gene is associated with shorter clinical outcome in prostate cancers.
Highlights
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancerrelated death among males worldwide [1]
We demonstrated that pyruvate dehydrogenase (PDHA1) gene knock out (KO) significantly decreased mitochondrial oxidative phosphorylation (OXPHOS) and promoted anaerobic glycolysis, accompanied with higher stemness phenotype including resistance to chemotherapy, enhanced migration ability and increased expression of cancer stem cell markers
We examined PDHA1 protein expression in prostate cancer tissues by immunohistochemistry and observed that reduced PDHA1 protein expression in clinical prostate carcinomas was significantly correlated with poor prognosis
Summary
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancerrelated death among males worldwide [1]. Similar to many other malignant tumors, the clinical management of prostate cancer is still challenging due to distant metastasis, chemoresistance and relapse. Accumulating evidence shows that cancer stem cells (CSCs) are likely to play key roles in tumor relapse and metastasis, which are thought to be one of the promising targets for cancer therapy. Wherein glycolysis is drastically upregulated with concomitantly increased lactate acid production even in the presence of oxygen, is proven to be nearly universally prevalent in most of cancers. It was reported that in this metabolism reprogram, specific genes involved in carbohydrate metabolism in tumors lead to both upregulation of glycolysis in the cytosol and downregulation of glucose oxidation by the mitochondria [2,3,4]. The molecular mechanism behind Warburg effect in tumors is still not fully explored
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