BubR1 is a critical regulator for the Taxol-induced mitochondrial cell death in human colon and breast cancer cells

Abstract

We previously have shown that BubR1 controls both mitotic checkpoint and cell death in response to microtubule disturbing agents. Here, we further examined whether BubR1 functions as a critical regulator of taxol, a microtubule stabilizing anticancer agent-induced cell death in human colon and breast cancer cells. We showed that there was a significant correlation between taxol sensitivity and BubR1 expression in human colon and breast cancer cells. Small interfering RNA (siRNA) targeting of BubR1 clearly attenuated taxol-induced conformational activation of Bax and Bak, and mitochondrial cell death. Conversely, cells overexpressing BubR1 were more sensitive to taxol treatment, and also showed enhanced Bax and Bak activation. We also found that BubR1 was directly translocated to the mitochondrial membrane and subsequently interacted with Bcl-2 and Bcl-XL, resulting inhibition of binding affinities of Bcl-2 and Bcl-XL to Bax or Bak in response to taxol treatment. These results indicate that BubR1 plays an important role in taxol-induced mitochondrial cell death through Bax and Bax activation and direct interaction with Bcl-2 and Bcl-XL. Our results suggest that BubR1 has the potential to be a molecular determinant for taxol sensitivity in human colon and breast cancer cells.