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Microtubules are the target of many anticancer drugs. Understanding the mechanism by which cells respond to different microtubule-targeted drugs is important to resolve the drug resistance and to gain better tumor control. We report here for the first time that CHK1, an essential protein in mammalian cells, affects cell sensitivity to microtubule-targeted drugs. By using a pair of transformed rat fibroblast cell lines, we show that compared with their counterpart B4 cells, A1-5 cells with higher CHK1 expression are more resistant to taxotere, a microtubule stabilizer, but are more sensitive to nocodazole, a microtubule destabilizer. We also show that the altered sensitivities of A1-5 cells to either taxotere or to nocodazole are related to the lesser microtubule-formation in the cells. In addition, we show that the altered drug sensitivities and less microtubules-formation shown in A1-5 cells could be efficiently reversed by Chk1 siRNA. Taken together, these results indicate that CHK1 is one of the factors affecting cell resistance to taxotere and sensitiveness to nocodazole, suggesting that CHK1 is involved in affecting microtubule dynamics and could be inhibited for taxotere sensitization in CHK1 highly expressed tumor cells. 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Fragile Histidine Triad (Fhit) gene deletion, methylation, and reduced Fhit protein expression occur in about 70% of human epithelial tumors and, in some cancers, are clearly associated with tumor progression. Specific Fhit signal pathways have not been identified, although it has been shown that Fhit overexpression leads to apoptosis in many cancer cell lines. We report in this study that Fhit−/− cells derived from gene knockout mice show much stronger S and G2 checkpoint responses than their wild type counterparts. The strong checkpoint responses are regulated by the ATR/CHK1 pathway, which contributes to the radioresistance of Fhit−/− cells. These results indicate an association of Fhit gene inactivation with increased survival after DNA damage, which is related to the over‐active checkpoints regulated by the ATR/CHK1 pathway. These results also suggest the potential effects of Fhit‐dependent DNA damage response on tumor progression. © 2004 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]