Role of parkin as a tumor suppressor protein in cervical cancer cells resistant to tumor necrosis factor-alpha

Abstract

Parkin is a putative tumor suppressor protein. Various types of cancers exhibit reduced expression of parkin or mutation in the parkin gene (PARK2). Many malignant tumors become resistant to tumor necrosis factor-alpha (TNF-α) during carcinogenesis, thus can escape from TNF-α-induced cell death. In the present study, I examined whether parkin acts as a tumor suppressor in HeLa cells, a human cervical cancer cell line resistant to TNF-α-induced cell death. TNF-α-treatment alone did not affect HeLa cell viability. However, expression of parkin restored TNF-α-induced apoptosis in HeLa cells. Increased cell death was due to activation of the apoptotic pathway. Expression of parkin in TNF-α-treated HeLa cells stimulated cleavage of the pro-apoptotic proteins caspase-8, -9, -3, -7 and poly ADP ribose polymerase (PARP). In addition, parkin expression resulted in decreased expression of the caspase inhibitory protein, survivin and the positive regulator of survivin, β-catenin. Inhibition of the PKC pathway resulted in restoration of β-catenin and survivin levels. These results suggest that parkin acts as a tumor suppressor through the PKC─β-catenin─survivin─caspase pathway. I propose that this pathway is a novel molecular mechanism by which parkin functions as a tumor suppressor.