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Modulation of paclitaxel resistance by annexin IV in human cancer cell lines
E K Han1, S K Tahir, S P Cherian
1Cancer Research, Department 4N6, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Abstract:
A recurring problem with cancer therapies is the development of drug resistance. While investigating the protein profile of cells resistant to a novel antimitotic compound (A204197), we discovered an increase in annexin IV expression. When we examined the annexin IV protein expression level in a paclitaxel-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 annexin IV staining in the nucleus starting at day 1. Furthermore, cells pretreated with 10 nM paclitaxel for 4 days resulted in cells becoming approximately fivefold more resistant to paclitaxel. Transfection of annexin IV cDNA into 293T cells revealed that there was a threefold increase in paclitaxel resistance. Thus our results indicate that annexin IV plays a role in paclitaxel resistance in this cell line and it is among one of the earliest proteins that is induced in cells in response to cytotoxic stress such as antimitotic drug treatment.
Insights
Annexin IV expression increases in cancer cells developing resistance to paclitaxel, a chemotherapy drug. This protein plays a key role in early drug resistance, offering a potential target for overcoming treatment failure.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Drug resistance is a major challenge in cancer therapy.
- Investigating protein changes in resistant cells is crucial for understanding resistance mechanisms.
Purpose of the Study:
- To identify proteins involved in paclitaxel resistance.
- To elucidate the role of annexin IV in the development of drug resistance.
Main Methods:
- Proteomic analysis of drug-resistant cancer cells.
- Immunostaining to determine protein localization.
- Gene transfection to assess functional impact on drug resistance.
Main Results:
- Annexin IV, but not annexin II, was overexpressed in paclitaxel-resistant cells.
- Annexin IV localized to the nucleus in resistant cells.
- Increased annexin IV expression correlated with increased paclitaxel resistance.
Conclusions:
- Annexin IV is upregulated in response to cytotoxic stress and contributes to paclitaxel resistance.
- Annexin IV is an early marker of cellular response to antimitotic drugs.