Abstract 269: A novel mechanism of p21 induction by oxaliplatin in p53 deficient cancer cells

Abstract

Abstract p21(CDKN1A) is a well known cyclin-dependent kinase (cdk) inhibitor. As a critical cell cycle checkpoint of p53 mediated DNA damage response, p21 interferes with cyclin-CDK2 complex, blocking cell cycle at the G1/S interface, thus reducing the risk of DNA damaged cells transforming to cancer cells. Activation of p21 checkpoint by therapeutic agent is often associated with cancer cell cycle arrest and effective tumor suppression. However, many cancer lost wild type p53 while p21 in these cells maintains at a low level. In these cells p21 transcription is mainly controlled by p53-independent mechanisms through various cis-acting elements and these type of cancer are often more likely to resist chemo treatment. In search of effective therapeutic agents against p53 negative and drug resistant cancers we used SKOV3, a p53 deficient cancer cell line, to assess the ability of common therapeutic drugs to induce p21 expression. Promoter-reporter assays suggest p21 promoter is significantly stimulated by Oxaliplatin in SKOV3 cells compared with most common drugs used in chemotherapy. Through the promoter deletion analysis we identified a previously unreported Oxaliplatin responsive cis-acting element located between −237 to −220bp in the p21 promoter. Genomic DNA functional element analysis using ENCODE (Encyclopedia of DNA Elements) Consortium suggests that a vertebrate-conserved element overlaps well with the newly discovered Oxaliplatin responsive element. This conserved promoter element is required for the effective induction of p21 promoter activity by Oxaliplatin and such induction is positively related to drug induced S-phase cell cycle arrest. Finally, the ability of p21 induction of chemotherapy drugs is well correlated with their effectiveness of reducing SKOV3 xenograft tumors in nude mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 269. doi:1538-7445.AM2012-269