Modulation of paolitaxel resistance by annexin IV in human cancer cell lines

A recurring problem with cancer therapies is the development of drug resist ance. While investigating the protein profile of cells resistant to a novel antimitotic compound (A204197), we discovered an increase in annexin IV ex pression. When we examined the annexin IV protein expression level in a pac litaxel-resistant cell line (H460/T800), we found that annexin IV was also overexpressed. Interestingly a closely related protein, annexin II, was not overexpressed in H460/T800 cells. Immunostaining with either annexin II or IV antibody revealed that annexin IV was primarily located in the nucleus of paclitaxel-resistant H460/T800 cells. Short-term treatment of H460 cells with 10 nM paclitaxel for up to 4 days resulted in induction of annexin IV , but not annexin II expression. In addition, there was an increase in anne xin IV staining in the nucleus starting at day 1. Furthermore, cells pretre ated with 10 nM paclitaxel for 4 days resulted in cells becoming similar to fivefold more resistant to paclitaxel. Transfection of annexin IV cDNA int o 293T cells revealed that there was a threefold increase in paclitaxel res istance. Thus our results indicate that annexin IV plays a role in paclitax el resistance in this cell line and it is among one of the earliest protein s that is induced in cells in response to cytotoxic stress such as antimito tic drug treatment. (C) 2000 Cancer Research Campaign.