Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Cancer Cells

Although lipids contribute to cancer drug resistance, it is challenging to target diverse range of lipids. Here we show enzymatically inserting exceedingly simple synthetic lipids into membranes for increasing membrane tension and selectively inhibiting drug resistant cancer cells. The lipid, formed by conjugating dodecylamine to D-phosphotyrosine, self-assembles to form micelles. Enzymatic dephosphorylation of the micelles inserts the lipids into membranes and increases membrane tension. This transformation of micelles effectively inhibits a drug resistant glioblastoma cell (T98G) or a triple-negative breast cancer cell (HCC1937), without inducing acquired drug resistance. Moreover, the enzymatic reaction of the micelles promotes the accumulation of the lipids in the membranes of subcellular organelles (e.g., endoplasmic reticulum (ER), Golgi, and mitochondria), thus activating multiple regulated cell death pathways. This work, as the first report that a multiple step molecular process increases membrane tension for inhibiting cancer cells, illustrates a new and powerful supramolecular approach for antagonizing difficult drug targets.