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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Klampfer L,Swaby LA,Huang J,Sasazuki T,Shirasawa S,Augenlicht Ldoi
10.1038/sj.onc.1208552subject
Has Abstractpub_date
2005-06-02 00:00:00pages
3932-41issue
24eissn
0950-9232issn
1476-5594pii
1208552journal_volume
24pub_type
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