Inhibition of hTERT expression by MAP kinase inhibitor induces cell death in renal cell carcinoma

Abstract

BackgroundHuman telomerase reverse transcriptase (hTERT) is one of the components of telomerase enzyme and its activity is associated with cell proliferation and differentiation. Extracellular signal regulated kinase (ERK)-mitogen activated protein kinase signaling pathway play an important role in hTERT expression. The present study was conducted to ascertain hTERT messenger RNA (mRNA) expression in renal cell carcinoma (RCC) and its association with clinicopathological characteristics. Further, we also explored hTERT targeting as possible tumor therapeutic. MethodsA total of 96 histopathologically confirmed RCC cases and corresponding normal tissues were subjected to hTERT gene expression using real-time PCR. Two RCC cell lines viz. ACHN and A498 were treated with MEK inhibitor (U0126) and hTERT mRNA expression, telomerase activity, cell viability, migration, and apoptosis were evaluated. ResultsThe hTERT mRNA levels were found to be significantly higher in RCC as compared with corresponding normal renal tissues (P = 0.040) as well as in high grades to that of low grades clear cell RCC (P = 0.008). Significantly diminished ERK phosphorylation and hTERT mRNA expression concomitantly reduced telomerase activity that was observed after U0126 treatment. Subsequently, cell viability and migration were significantly inhibited after treatment with U0126 in both the cell lines to that of control (P = 0.001). In addition, U0126-treated cells showed significantly increased apoptosis (P = 0.001) to that of controls. ConclusionHenceforth, this study infer that, hTERT expression can be used as a possible diagnostic marker for RCC, and inhibition of hTERT expression by hampering ERK-mitogen activated protein kinase cascade may be used as a promising anticancer target in RCC.