Abstract
BackgroundTaxol is a microtubule stabilizing agent that arrests cells in mitosis leading to cell death. Taxol is widely used to treat breast cancer, but resistance occurs in 25–69% of patients and it is vital to understand how Taxol resistance develops to improve chemotherapy. The effects of chemotherapeutic agents are overcome by survival signals that cancer cells receive. We focused our studies on autotaxin, which is a secreted protein that increases tumor growth, aggressiveness, angiogenesis and metastasis. We discovered that autotaxin strongly antagonizes the Taxol-induced killing of breast cancer and melanoma cells by converting the abundant extra-cellular lipid, lysophosphatidylcholine, into lysophosphatidate. This lipid stimulates specific G-protein coupled receptors that activate survival signals.Methodology/Principal FindingsIn this study we determined the basis of these antagonistic actions of lysophosphatidate towards Taxol-induced G2/M arrest and cell death using cultured breast cancer cells. Lysophosphatidate does not antagonize Taxol action in MCF-7 cells by increasing Taxol metabolism or its expulsion through multi-drug resistance transporters. Lysophosphatidate does not lower the percentage of cells accumulating in G2/M by decreasing exit from S-phase or selective stimulation of cell death in G2/M. Instead, LPA had an unexpected and remarkable action in enabling MCF-7 and MDA-MB-468 cells, which had been arrested in G2/M by Taxol, to normalize spindle structure and divide, thus avoiding cell death. This action involves displacement of Taxol from the tubulin polymer fraction, which based on inhibitor studies, depends on activation of LPA receptors and phosphatidylinositol 3-kinase.Conclusions/SignificanceThis work demonstrates a previously unknown consequence of lysophosphatidate action that explains why autotaxin and lysophosphatidate protect against Taxol-induced cell death and promote resistance to the action of this important therapeutic agent.
Highlights
Breast cancer is the most common malignancy among women in Western societies and approximately 30% of breast cancer patients develop metastases and die [1]
To investigate how LPA antagonizes the Taxol-induced arrest in G2/M and subsequent cell death [7], we determined if LPA affects cell cycle progression or induces selective killing of cells arrested in mitosis by Taxol
Neither does LPA decrease the Taxol-induced accumulation of MCF-7 cells in mitosis by delaying entry into G2/M or by inducing selective death of the cells arrested in mitosis
Summary
Breast cancer is the most common malignancy among women in Western societies and approximately 30% of breast cancer patients develop metastases and die [1]. LPA strongly antagonizes Taxol-induced death in MCF-7 breast cancer and MDA-MB-435 melanoma cells [7] This effect requires the activation of phosphatidylinositol 3-kinase (PI3K) and it is accompanied by a reversal of the Taxol-induced increase in ceramide concentrations. Ceramides are bioactive lipids that cause increased apoptosis in most cells [9] They accumulate in cancer cells in response to a large variety of chemotherapeutic agents and radiation therapy as part of the process leading to caspase activation and cell death [10,11,12]. We discovered that autotaxin strongly antagonizes the Taxol-induced killing of breast cancer and melanoma cells by converting the abundant extra-cellular lipid, lysophosphatidylcholine, into lysophosphatidate. This lipid stimulates specific G-protein coupled receptors that activate survival signals
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