Lipid metabolism and Calcium signaling in epithelial ovarian cancer

Possible links between Ca2+ channels and Ca2+-activated potassium channels associated with cancer progression and the two major lipids, arachidonic acid (AA) and lysophosphatidic acid (LPA) implicated in ovarian cancer. LPA acts as a potent extracellular signaling molecule through its receptors: LPAR 1-5 are all coupled to Gαq/11 activating the Phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 binds to its receptor in the ER and initiates calcium release from stores. Ca2+ depletion is sensed by STIM1 that interacts with ORAI channels at the plasma membrane inducing Ca2+ entry. This Ca2+ entry activates other channels of which the Ca2+ activated potassium channels (KCa) and the Ca2+ influx is therefore potentiated by hyperpolarization. STIM can also interact with other Ca2+ channels such as TRPC1/4/5 channels. On the other hand, the DAG released from PIP2 hydrolysis, can also participate in Ca2+ entry via other TRP channels such as TRPC3/C6. DAG metabolism generates other messengers such as the Arachidonic Acid (AA) that has been proved to induce Ca2+ entry in a store independent manner via other TRP channels or ORAI multimeric channels. Note that extracellular AA could also be easily imported into the tumor cell by the expression of fatty acid carriers such as CD36 and FATP4 that contribute to tumor progression and metastasis by modulating ion channels activity. Deregulated Ca2+ influx in the cancer cells is necessary for proliferation, survival and migration/invasion. The precursor phospholipids can be converted to their corresponding lysophospholipids. This occurs via phosphatidylserine-specific phospholipase A1 (PLA1) or secretory phospholipase A2 (PLA2) activity. Lysophospholipids are then converted to LPA via autotaxin (ATX) activity. In the second major pathway, phosphatidic acid (PA) is first produced from phospholipids through phospholipase D. PA is then converted directly to LPA by the actions of either PLA1 or PLA2