Abstract 5191: Missense mutants of p53 tumor suppressor contributes to drug-resistance and epithelial-mesenchymal transition in colon cancer cells

Abstract

Abstract The mutants of p53 tumor suppressor that have been detected in approximately 50% of tumors exhibit oncogenic function and promote tumor progression. Restoration of tumor suppression by introduction of wild-type p53 effectively eliminate cancers in preclinical studies; however, more than 80% of p53 mutations are missense mutants, those can form heterotetramers and diminish the therapeutic effect of p53 transgene. It is still unclear how missense mutants promote tumor progression, particularly in whether or not these mutants contribute to induced cancer stem cells during chemotherapy. We report herewith that R273 missense mutant contributes to drug-induced stem cell-like behavior in colorectal cancer cells. Heterozygous SW48 TP53 (R273H/+) cells presented the same sensitivity to doxorubicin and paclitaxel as its parental SW48 colon cancer cells. However, after exposure to lower concentrations of doxorubicin (10 nM) or paclitaxel (4 nM) for eight weeks, SW48 TP53 not only were resistant to anticancer drugs, but also displayed an epithelial-mesenchymal transition (EMT). With the overexpressed E-cadherin and down-expressed vimentin, SW48 TP53 cells that were exposed to doxorubicin displayed significantly EMT morphological changes and increased wound healing, compared to SW 48 cells. Interestingly, inhibition of ceramide glycosylation with PDMP to increase endogenous ceramide restored wild-type p53 expression in heterozygous SW48 TP53 cells exposed to doxorubicin and further sensitized these cells to anticancer drugs and reversed EMT. These findings indicate that a heterozygous missense p53 mutant promotes EMT and drug resistance of colon cancer cells in chemotherapy, and restoration of p53 expression with suppression ceramide glycosylation can improve therapeutic efficacy. Citation Format: Salman B. Hosain, Yong Y. Liu. Missense mutants of p53 tumor suppressor contributes to drug-resistance and epithelial-mesenchymal transition in colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5191. doi:10.1158/1538-7445.AM2015-5191