Lysophosphatidate Induces Chemo-Resistance by Releasing Breast Cancer Cells from Taxol-Induced Mitotic Arrest

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.

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

“…Over the course of two decades of research, a large number of studies have established that in addition to cellautonomous cancer hallmarks such as differentiation ( 58,(103)(104)(105)(106), survival (107)(108)(109)(110)(111)(112), proliferation ( 58,(113)(114)(115)(116), and migration/metastatic behavior ( 50, 74,92,[117][118][119][120][121][122], the aberrant expression/amplifi cation of ATX activity can also dysregulate multiple cancer pathobiology systemic hallmarks including angiogenesis ( 119,123 ), metabolic homeostasis ( 56-59, 104, 124, 125 ), and immune system function ( 126 ).…”

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice

“…Expressions of LPPs and LPA 1 and LPA 2 receptors were determined by real-time RT-PCR ( 8 ). Western blotting and immunohistochemistry were performed as described previously ( 13 ).…”

Inhibition of NF-κB activation improves insulin resistance of L6 cells

“…Triplicate samples were prepared for each treatment, and 200 cells were counted in random fields for each sample. Then the percentage of apoptotic nuclei was calculated [16].…”