Abstract 3470: The antagonistic functional duality of p21WAF1/CIP1 in cells derived from multicellular tumor spheroids

Abstract

Abstract The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a key mediator of p53-dependent cell cycle arrest after DNA damage, in addition to p53-independent mechanisms. Being one of the major transcriptional targets of p53 and due to its anti-cell proliferative activity, p21 was considered initially as a potent tumor suppressor. However, emerging studies now show the anti-apoptotic and pro-cell proliferative effects of p21, highlighting the oncogenic role of p21 in cancer. In particular, p21 results in genomic instability and the development of aggressive and chemo-resistant traits in a subset of highly proliferating tumor cells through p53-independent pathways. The cellular localization of p21 has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Herein, using a combination of gene knockout, cytotoxicity assay, immunofluorescence, immunoprecipitation, and mass spectrometry techniques, we study the consequence of nuclear and cytoplasmic localization of p21 on cell survival and drug response in cells derived from multicellular spheroids of multiple human cancer cell lines. Our study shows that cells derived from multicellular spheroids show an increased induction of p21 despite the reversal from three-dimensional to two-dimensional cultures. The p21-overexpressing, highly proliferative cells are significantly resistant to a number of standard anti-cancer agents. Further analysis shows that the majority of p21 in this subset of spheroid-derived cells is localized in the cytoplasm and forms a potential 'anti-apoptosome'-like complex with mitochondrial apoptosis-associated proteins. These findings add to the shifting paradigm on the oncogenic role p21 due to cellular mislocalization in tumor cells. Citation Format: Viswanath Das, Narendran Annadurai, Dušan Holub, Marián Hajdúch. The antagonistic functional duality of p21WAF1/CIP1 in cells derived from multicellular tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3470.