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Oncogenic Ras increases sensitivity of colon cancer cells to 5-FU-induced apoptosis

Oncogene volume 24, pages 3932–3941 (2005)Cite this article

Abstract

Despite the fact that objective response rates to 5-FU are as low as 20%, 5-FU remains the most commonly used drug for the treatment of colorectal cancer. The lack of understanding of resistance to 5-FU, therefore, remains a significant impediment in maximizing its efficacy. We used intestinal epithelial cells with an inducible K-RasV12 to demonstrate that expression of oncogenic Ras promotes cell death upon 5-FU treatment. Accordingly, transient expression of the mutant RasV12, but not the WT Ras, enhanced 5-FU-induced apoptosis in 293T cells. Consistent with these data, we showed that targeted deletion of the mutant Ras allele in the HCT116 colon cancer cell line protected cells from 5-FU-induced apoptosis. Using isogenic colon cancer cell lines that differ only by the presence of the mutant Ras allele, HCT116 and Hke-3 cells, we demonstrated that signaling by oncogenic Ras promotes both accumulation of p53 and its phosphorylation on serine15 in response to 5-FU, a situation that favors apoptosis over growth arrest. However, despite the differential induction of p53 in HCT116 and Hke-3 cells, the expression of Puma, a gene with an important role in p53-dependent apoptosis, was not affected by Ras signaling. In contrast, we showed that Ras interferes with 5-FU-induced expression of gelsolin, a protein with known antiapoptotic activity. We ascertained the role of gelsolin in 5-FU-induced apoptosis by demonstrating that silencing of gelsolin expression through RNAi sensitized cells to 5-FU-induced apoptosis and that re-expression of gelsolin in cells harboring mutant Ras protected cells from 5-FU-induced apoptosis. These data therefore demonstrate that Ras mutations increase sensitivity to 5-FU-induced apoptosis at least in part through the negative regulation of gelsolin expression. Our data indicate that Ras mutations promote apoptosis in response to 5-FU treatment and imply that tumors with Ras mutations and/or reduced expression of gelsolin may show enhanced apoptosis in response to 5-FU also in vivo.

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Acknowledgements

This study was supported by the Montefiore Medical Center New Research Initiative Award to LK and the American Cancer Society Institutional Research Grant to LK (ACS IRG #98-274-01), UO1 CA88104 (to LA) and P30-13330 from NCI.

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Authors and Affiliations

  1. Albert Einstein Cancer Center, Montefiore Medical Center, Department of Oncology, Bronx, NY, 10467, USA

    Lidija Klampfer, Laurie-Anne Swaby, Jie Huang & Leonard Augenlicht

  2. Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo, 162-8655, Japan

    Takehiko Sasazuki & Senji Shirasawa

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  1. Lidija Klampfer
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  2. Laurie-Anne Swaby
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Correspondence to Lidija Klampfer.

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Klampfer, L., Swaby, LA., Huang, J. et al. Oncogenic Ras increases sensitivity of colon cancer cells to 5-FU-induced apoptosis. Oncogene 24, 3932–3941 (2005). https://doi.org/10.1038/sj.onc.1208552

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