Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells.

Jiaqing Wang, Weiyi Tan, Guanying Li, Difei Wu, Hongjian He, Jiashu Xu, Meihui Yi, Ye Zhang, S Ali Aghvami, Seth Fraden, Bing Xu

Chemistry (Weinheim an der Bergstrasse, Germany) 2020 Nov 26

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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. The micelles effectively inhibit 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, in which for the first time membrane tension is increased to inhibit cancer cells, illustrates a new and powerful supramolecular approach for antagonizing difficult drug targets. © 2020 Wiley-VCH GmbH.

Citation

Jiaqing Wang, Weiyi Tan, Guanying Li, Difei Wu, Hongjian He, Jiashu Xu, Meihui Yi, Ye Zhang, S Ali Aghvami, Seth Fraden, Bing Xu. Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells. Chemistry (Weinheim an der Bergstrasse, Germany). 2020 Nov 26;26(66):15116-15120