engleski

THE ROLE OF P21WAF1/CIP1 GENE IN AUTOPHAGY AND SENESCENCE IN TUMOR CELLS

Autophagy is a process of lysosomal degradation of cellular components operating in physiological conditions, but it can also be activated as a stress response. Cellular senescence, an irreversible cell cycle arrest can be induced with certain chemotherapeutics to accomplish tumor growth inhibition. Recently, it was discovered that autophagy might mediate mitotic senescence transition. Due to apoptotic cell death deficiencies, chemoresistance often occurrs in tumor cells. Therefore, senescence and autophagy are becoming potential alternative mechanisms for antitumor therapy. p21WAF1/Cip1 is a well characterized cyclin-dependent kinase inhibitor that negatively modulates the cell cycle progression by arresting G1, G2 or S cell-cycle phases. p21 has a role in cell differentiation, senescence and apoptosis, where it can act as either inhibitor or activator of apoptosis. However, its role in autophagy is completely underexplored and only recently addressed. The aim of this study was to investigate if autophagy and cellular senescence are activated upon p21 overexpression. In addition, the influence of cisplatin treatment-response upon p21 gene overexpression was assessed. SW480 and HCT116 colon cancer cells were treated with cisplatin and adenovirus-mediated p21 overexpression was induced. Both treatments alone or in combination induced autophagy and senescence thereby preventing tumor growth. It was demonstrated that autophagy modulation influences senescence induction. However, downregulation of the basal p21 gene expression had no statistically significant influence on autophagy modulation, while it inhibited senescence activation upon cisplatin treatment. These results give additional insights into interconnected mechanisms of cell-responses to therapy and determine whether and how p21 characterizes chemosensitivity of tumor cells.

p21; autophagy; senescence; chemosensitivity

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