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KLF5 is a transcription factor that has been linked to enhanced proliferation in multiple non-transformed cell types. In contrast to its growth promoting role in non-transformed cells, KLF5 has been implicated as a tumor suppressor in epithelial tissues including the intestine. An explanation for this paradox comes from the observation that, while KLF5 promotes colony formation in non-transformed intestinal epithelial cells, it inhibits this process in colon cancer cells. These opposing effects were further characterized by manipulating KLF5 expression in various intestinal epithelial cell lines. Retroviral mediated overexpression of KLF5 in HCT-116 and HCT-116b colon cancer cells, but not in non-transformed IEC-18 cells, led to cell death characterized by the appearance of blebbing and shrunken cells, that was not seen in control virus transduced cells. This cells death was due to apoptosis, as indicated by its inhibition by the pan-caspase inhibitor Z-VAD-FMK and by annexin V staining. A link between the observed apoptosis and KLF5 expression was further established by the finding that siRNA-mediated knockdown of KLF5 expression reduced the level of spontaneous apoptosis/annexin V staining in HCT-116b cells (colon carcinoma cells that express relatively high levels of KLF5). The differential ability of KLF5 to induce apoptosis cannot be attributed to genetic differences between the cell lines examined because, in contrast to parental IEC-18 cells, KLF5 induced apoptosis in IEC-18 cells which had been transformed with oncogenic H-Ras (IEC-Ras cells). Notably, the farnesyl-transferase inhibitor L-744,832 blocked the ability of KLF5 to induce apoptosis in Ras-transformed IEC-18 cells. By inhibiting signaling from oncogenic H-Ras but not endogenous K-Ras, this inhibitor reverses the transformed phenotype without appreciable affects on survival or proliferation of H-Ras transformed IEC-18 cells; thus, this finding links both the transformed phenotype and Ras signaling to the differential ability of KLF5 to induce apoptosis in non-transformed and transformed intestinal epithelial cells. Analysis of molecular mechanisms underlying KLF5-induced apoptosis point to the involvement of alterations in inhibitor of apoptosis proteins XIAP and survivin. This work was supported by NIH grant CA16056.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]