Abstract
Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. However, the molecular mechanism underlying the function of PKM2 in renal cancer is undetermined. Here, we reveal the overexpression of PKM2 in the proximal tubule of renal tumor tissues from 70 cases of patients with renal carcinoma. The functional role of PKM2 in human renal cancer cells following small-interfering RNA-mediated PKM2 knockdown, which retarded 786-O cell growth was examined. Targeting PKM2 affected the protein kinase B (AKT)/mechanistic target of the rapamycin 1 (mTOR) pathway, and downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, and other downstream signaling key proteins. PKM2 knockdown changed glycolytic metabolism, mitochondrial function, adenosine triphosphate (ATP) level, and intracellular metabolite formation and significantly reduced 786-O cell migration and invasion. Acridine orange and monodansylcadaverine staining, immunocytochemistry, and immunoblotting analyses revealed the induction of autophagy in renal cancer cells following PKM2 knockdown. This is the first study to indicate PKM2/AKT/mTOR as an important regulatory axis mediating the changes in the metabolism of renal cancer cells.
Highlights
Renal cell carcinoma (RCC) is the most common type of kidney cancer, and approximately 64,000 new cases were diagnosed in the United States of America in 2017 [1,2]
We investigated whether pyruvate kinase M2 (PKM2) promotes the progression of clear cell renal cell carcinoma (ccRCC) tumorigenesis and the mechanism underlying PKM2-mediated regulation of cancer cell metabolism to understand the molecular mechanisms involved in RCC development
We performed IHC to investigate the expression of PKM2 protein in a cohort of 70 tissue samples derived from patients with kidney cancer and 10 nontumor tissues
Summary
Renal cell carcinoma (RCC) is the most common type of kidney cancer, and approximately 64,000 new cases were diagnosed in the United States of America in 2017 [1,2]. Among the main histological subtypes of RCC, clear cell renal cell carcinoma (ccRCC) is deemed as the most hostile, responsible for 70–80% of all RCC cases [3,4]. The resistance of cancer cells to chemotherapy and radiation therapy demands the development of new therapeutic strategies [7]. The development of targeted therapeutics, including multitargeted tyrosine kinase (TK) and mechanistic target of rapamycin 1 (mTOR) inhibitors, has been a major breakthrough in the discovery of interventions against ccRCC [7]. New therapeutic strategies have emerged as effective treatment options against advanced ccRCC through the reprogramming of cancer cell metabolism and use of glycolysis inhibitors [8]
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