Blocking Ether Lipid Synthesis Prevents Tumor Growth

Tumor cells have elevated levels of ether lipids, and blocking the activity of an enzyme critical to their synthesis was found to have profound anticancer benefits.

Levels of ether lipids, which are lipids in which one or more of the carbon atoms on glycerol is bonded to an alkyl chain via an ether linkage as opposed to the usual ester linkage, are higher in tumors than in normal tissues, but their specific function in cancer has remained unclear.

In a recent study, investigators at the University of California, Berkeley (USA) looked at the metabolism of ether lipids and the ramifications of interfering with their synthesis.

They reported in the August 26, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), which catalyzes a critical step in the synthesis of ether lipids, was upregulated across multiple types of aggressive human cancer cells and primary tumors. Inhibition of AGPS in cancer cells resulted in reduced cell survival, cancer aggressiveness, and tumor growth through altering the balance of ether lipid, fatty acid, eicosanoid, and fatty acid-derived glycerophospholipid metabolism, resulting in an overall reduction in the levels of several oncogenic signaling lipids.

"Cancer cells make and use a lot of fat and lipids, and that makes sense because cancer cells divide and proliferate at an accelerated rate, and to do that, they need lipids, which make up the membranes of the cell," said senior author Dr. Daniel Nomura, assistant professor of nutritional sciences and toxicology at the University of California, Berkeley. "The cancer cells were less able to move and invade. Lipids have a variety of uses for cellular structure, but what we are showing with our study is that lipids can also send signals that fuel cancer growth."

The investigators also evaluated the impact of inhibiting AGPS in mice that had been injected with cancer cells. "Among the mice that had the AGPS enzyme inactivated, the tumors were nonexistent," said Dr. Nomura. "The mice that did not have this enzyme disabled rapidly developed tumors."

Research is now underway to develop AGPS inhibitors for use in cancer therapy.

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