Hypoxia inducible factor‐1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions

Paclitaxel (PTX) is an anticancer drug that is effective against a wide range of solid tumors. The effect of PTX on two human lung cancer cell lines, PC14PE6 and NCI‐H441 cells, was examined in an orthotopically transplanted animal model with an in vivo imaging devise. Although PTX effectively suppressed tumor growth and improved survival rate in NCI‐H441, it did not influence these in PC14PE6. In vitro experiments confirmed that PC14PE6 cells are resistant to PTX under normoxic conditions and that both cell lines were resistant to PTX under hypoxic conditions. It was found that the expression level of endogenous hypoxia inducible factor (HIF)‐1α in PC14PE6 is much higher than that in NCI‐H441 cells under normoxic conditions. Furthermore, sensitivity to PTX in these cell lines was reversed when HIF‐1α expression was decreased by siRNA specific to HIF‐1α in PC14PE6 and increased by overexpression of the exogenous HIF‐1α gene in NCI‐H441. These results suggest that HIF‐1 influences the PTX sensitivity of these cells. The authors further examined β‐tubulin, a target molecule of PTX, with western blotting and immunohistochemical analysis in these cells. The expression level of β‐tubulin was comparable in these cells under both normoxic and hypoxic conditions while the distribution of β‐tubulin and cell morphology were changed according to HIF‐1α expression levels, suggesting that HIF‐1 influences the conformation and dynamics of microtubules. These data support the potential development of HIF‐1 targeted approaches in combination with PTX, where drug resistance tends to contribute to treatment failure. ( Cancer Sci 2007; 98: 1394–1401)