Ether-lipids and calcium signaling in metastases

Ether-lipids are lipids that possess anti-tumor properties and some of these molecules have been considered of potential use in the diagnosis of prostate cancer. Among these lipids, we have identified a family of new ether-lipids that can prevent metastasis development by modifying the activity of ion channel complexes (KCa-Ca2+) located in lipid rafts and regulating calcium signaling in cancer cells. Natural ether-lipids (as phospholipids or triglycerides or phospholipids) have a long fatty alcohol chain linked to the glycerol unit by an ether bond. In cell membranes, they form alkyl or alkenyl phospholipids (also referred to as plasmalogens). In tumors, they have been found in larger amount than in normal tissues but the physiological roles of these ether-lipids have not been elucidated so far and the clinical significance of their accumulation in tumors remains to be determined.
In tumors, because of the aberrant expression KCa and Ca2+ channels, calcium signaling becomes distorted. These alterations cause calcium homeostasis deregulation that promotes tumor cell migration and metastasis development. One of the calcium entry pathways regulating calcium homeostasis in cancer cells is triggered by the depletion of intracellular calcium stores, giving rise to store-operated calcium entry (SOCE) with STIM1, Orai1 and TRPC proteins forming store-operated calcium channels (SOC). An alternative route for Ca2+ entry is the store-independent Ca2+ entry (SICE) with either a constitutive calcium entry (through Orai1 or TRPV channels, independently of the STIM protein). Another possible calcium entry may be activated by agonists and arachidonic acid (AA) with Orai1 and Orai3 proteins and plasma membrane STIM1 forming ARC channels (Arachidonic acid Regulated Calcium channel).