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• W1969241505 abstract "Farnesyltransferase inhibitors (FTIs), small molecules that inhibit prenylation of multiple proteins such as Ras and Rho, have clinical promise for cancer. FTIs block malignant growth and promote cell death in a wide variety of tumor types in vitro and in vivo, but the mechanisms underlying the antitumor activity of FTIs are not completely understood. We have observed that colon cancer cell line OS187 responds to the FTI tipifarnib with a senescent phenotype, demonstrated as altered cell morphology, elevated senescence-associated β-galactosidase activity, upregulated protein and mRNA levels of senescence markers, and long-term cell cycle arrest. Our previous results also indicated that cells retaining intact p53 are more sensitive to tipifarnib than are cells with absent/inactive p53, suggesting a possible role for p53 in the senescent response to tipifarnib. To test this hypothesis, we used shRNA to reduce p53 expression in OS187 cells. Loss of p53 reversed the swollen and enlarged senescent-like cellular phenotype induced by tipifarnib. In addition, p53 knockdown cells showed less senescence-associated β-galactosidase activity than did scrambled control cells after 7-day treatment with tipifarnib. Cell viability assay suggested that p53 knockdown partially rescued the cytotoxic effects of tipifarnib at low concentrations. Western blot also demonstrated that cell cycle regulatory proteins such as p27, p21, and p15 were significantly upregulated in scrambled control cells while only a slight increase of these proteins were observed in p53 knockdown cells after tipifarnib treatment. Flow cytometry analysis showed that cells with decreased p53 level had a reduced percentage of cells in sub G1 phase when treated with a high concentration of tipifarnib, and fewer cells arresting in G2/M phase when treated with low concentration of tipifarnib compared to the scrambled control cells. This observation suggested that p53 may involve in different pathways depending on the strength of the stress signal imposed by different concentration of tipifarnib. In conclusion, these results confirm that p53 is important for inducing senescence when farnesylation is inhibited in OS187 cells. However, since p53 knockdown has very limited impact on the anti-proliferation effects of tipifarnib at high concentrations, other pathways are expected to play a role in mediating cell susceptibility to tipifarnib. Future experiments will focus on investigating the p53-independent pathways that are responsible for tipifarnib-induced senescence and apoptosis. 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 2876. doi:1538-7445.AM2012-2876" @default.
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• W1969241505 date "2012-04-15" @default.
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• W1969241505 title "Abstract 2876: Farnesyltransferase inhibitor induces p53-dependent cellular senescence in colon cancer cells" @default.
• W1969241505 doi "https://doi.org/10.1158/1538-7445.am2012-2876" @default.
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