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First-line treatment of breast and other cancers with Taxol is compromised by resistance in up to 40% of patients. To improve chemotherapy, it is vital to understand how Taxol resistance develops and to overcome this. Autotaxin (ATX) promotes cancer cell survival, growth, migration, invasion and metastasis. ATX converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). As these lipids have been reported to affect cell signaling through their own G-protein-coupled receptors, ATX could modify the balance of this signaling. Also, ATX affects cell adhesion independently of its catalytic activity, We first investigated the interactions of ATX, LPC and LPA on the apoptotic effects of Taxol, which is commonly used in breast cancer treatment. LPC had no significant effect on Taxol-induced apoptosis in MCF-7 breast cancer cells, which do not secrete significant ATX. Addition of incubation medium from MDA-MB-435 melanoma cells, which secrete ATX, or recombinant ATX enabled LPC to inhibit Taxol-induced apoptosis of MCF-7 cells. Inhibiting ATX activity blocked this protection against apoptosis. We conclude that LPC has no significant effect in protecting MCF-7 cells against Taxol treatment unless it is converted to LPA by ATX. LPA strongly antagonized Taxol-induced apoptosis through stimulating phosphatidylinositol 3-kinase and inhibiting ceramide formation. LPA also partially reversed the Taxol-induced arrest in the G2/M phase of the cell cycle. Then, we described a novel action of LPA, which by activating phosphatidylinositol 3-kinase increases the expression of glycogen synthase kinase-3 and survivin. Survivin is an anti-apoptotic protein, which also increases the dynamicity of microtubules. Survivin decreased the effectiveness of Taxol in stabilizing microtubules and enabled MCF-7 breast cancer cells to escape from Taxol-induced arrest in G2/M and consequent cell death. Our work showed that inhibiting ATX activity and LPA-mediated signaling can reverse the resistance to Taxol-induced cell death. Our results support the hypothesis that therapeutic inhibition of ATX activity, which results in less LPA production, or inhibition of LPA signalling could improve the efficacy of Taxol as a chemotherapeutic agent for cancer treatment. / Medical Sciences - Laboratory Medicine and Pathology

Increased expression of autotaxin has been shown to promote metastasis formation and cancer proliferation. These actions could be related to the catalytic activity of autotaxin which converts lysophosphatidylcholine into lysophosphatidate extracellularly or non-catalytic functions of autotaxin may be responsible. Also both LPC and LPA have been reported to stimulate migration through their respective receptors. This work investigates the role of autotaxin in controlling the motility of two cancer cell lines. With the use of autotaxin inhibitors we were able to block LPC-induced migration. Knocking-down autotaxin secretion also blocked stimulation of migration by LPC. Autotaxin inhibitors abolished any migratory effects from media collected from autotaxin secreting cells. We determined that LPC alone is unable to stimulate migration. Also we did not observe non-catalytic effects of autotaxin on migration. This thesis provides strong evidence that the inhibition of autotaxin production or activity would provide a beneficial therapy in the prevention of tumour growth or metastasis in patients with autotaxin expressing tumours.

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