Targeting lipid droplet lysophosphatidylcholine for cisplatin chemotherapy.

Abstract

This study aims to explore lipidic mechanism towards low-density lipoprotein receptor (LDLR)-mediated platinum chemotherapy resistance. By using the lipid profiling technology, LDLR knockdown was found to increase lysosomal lipids and decrease membranous lipid levels in EOC cells. LDLR knockdown also down-regulated ether-linked phosphatidylethanolamine (PE-O, lysosomes or peroxisomes) and up-regulated lysophosphatidylcholine [LPC, lipid droplet (LD)]. This implies that the manner of using Lands cycle (conversion of lysophospholipids) for LDs might affect cisplatin sensitivity. The bioinformatics analyses illustrated that LDLR-related lipid entry into LD, rather than an endogenous lipid resource (eg Kennedy pathway), controls the EOC prognosis of platinum chemotherapy patients. Moreover, LDLR knockdown increased the number of platinum-DNA adducts and reduced the LD platinum amount. By using a manufactured LPC-liposome-cisplatin (LLC) drug, the number of platinum-DNA adducts increased significantly in LLC-treated insensitive cells. Moreover, the cisplatin content in LDs increased upon LLC treatment. Furthermore, lipid profiles of 22 carcinoma cells with differential cisplatin sensitivity (9 sensitive vs 13 insensitive) were acquired. These profiles revealed low storage lipid levels in insensitive cells. This result recommends that LD lipidome might be a common pathway in multiple cancers for platinum sensitivity in EOC. Finally, LLC suppressed both cisplatin-insensitive human carcinoma cell training and testing sets. Thus, LDLR-platinum insensitivity can be due to a defective Lands cycle that hinders LPC production in LDs. Using lipidome assessment with the newly formulated LLC can be a promising cancer chemotherapy method.

• Authors: Lumin Chen, Wen-Lung Ma, Wei-Chung Cheng, Juan-Cheng Yang, Hsiao-Ching Wang, Yu-Ting Su, Azaj Ahmad, Yao-Ching Hung, Wei-Chun Chang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 13 Pg. 7187-7200 (07 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32543783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Liposomes
• Lysophosphatidylcholines
• Receptors, LDL
• Cisplatin

Topics

• Animals
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Female
• Humans
• Lipid Droplets (metabolism)
• Lipidomics
• Liposomes
• Lysophosphatidylcholines (metabolism)
• Mice, Nude
• Models, Biological
• Receptors, LDL (metabolism)