Abstract 2838: The role of cyclin D1-associated kinase activity in the regulation of autophagy and senescence in gastric cancer cells

Abstract

Abstract Introduction: Cyclin D1 regulates cell cycle progression through its ability to bind and activate cyclin-dependent kinases 4 and 6 (CDK4/6). Recent work carried out in mammary epithelial cells (MECs) propagated in vitro has revealed that the functional status of cyclin D1 modulates a balance between senescence and autophagy, two processes commonly disrupted in human cancers. Thus, in contrast to the commonly held assumption that autophagy is an effector process of senescence, inhibition of autophagy was accompanied by an induction or exacerbation of senescence in MECs deficient in cyclin D1-associated kinase activity, a reflection of the pro-survival function of autophagy in these cells. Materials and methods: In the present study, we set out to confirm these findings in gastric cancer cell lines (AGS, MKN-45 and KATO III) that may differ in their ability to induce senescence. To this end, we first treated AGS (cyclin D1+; pRB+; p53+) cells with Palbociclib (a specific inhibitor of cyclin D-CDK4/6 complexes), Spautin-1 (a specific inhibitor of autophagy), or a combination of these drugs, and assessed the effect of the treatment on the ability of these cells to proliferate or undergo senescence. Results and discussion: Unlike what was previously reported, our results suggest that autophagy is not required for the implementation of the senescent phenotype in AGS cells treated with Palbociclib. Nonetheless, senescent cells in which autophagy was disrupted were larger and often displayed multiple nuclei, suggesting the existence of different senescence programs depending on autophagy function. Citation Format: Leandro Vargas, Sindy Bravo, Claudio Valenzuela, Nelson E. Brown. The role of cyclin D1-associated kinase activity in the regulation of autophagy and senescence in gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2838.