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The role of p21WAF1/Cip1 gene in autophagy and senescence as responses to cisplatin treatment of colon carcinoma 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. It appears to be very important in tumor development, progression and chemosensitivity. Cellular senescence, an irreversible cell cycle arrest, usually occurs upon telomere shortening, but can also be induced with certain chemotherapeutics to accomplish tumor growth inhibition. Interestingly, 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 phase of the cell cycle. Moreover, 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. Because of its complex and contradictory functions, it is important to study its roles in different cell death responses to DNA-damage treatment. 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. Moreover, the role of p21 in autophagy mediated senescent transition was also investigated. SW480 and HCT116 colon cancer cells were treated with cisplatin upon adenovirus-mediated p21 overexpression. Both treatments alone or in combination induced autophagy and cellular 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. We hope that the discovery of precise mechanisms of cell-response to therapy and the role of p21 gene in their modulation could lead to the design of new and more effective treatments of cancer.

p21WAF1/Cip1; senescence; autophagy; cisplatin

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