Abstract
Platinum-based therapy remains the cornerstone for cancer patient management; however, its efficacy varies. Theis study demonstrated the differential expressions of low-density lipoprotein receptor (LDLR) in subtypes of epithelial ovarian carcinoma (EOC) determines cisplatin sensitivity. It’s sensitive in serous EOCs (low LDLR), where insensitive in endometrioid and clear cell EOCs (high LDLR). Meanwhile, knocked-down or overexpressed LDLR in EOC could reversed the chemosensitivity pattern both in vitro and in vivo. Mechanistic dissection with transcriptome vs. lipidome trans-omics analyses elucidated the LDLR→LPC (Lyso-PhosphotidylCholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis in cisplatin insensitivity. Implementing LPC-liposome encapsulated cisplatin could facilitate DNA-adduct formation via lipid droplets (LDs) delivery. Furthermore, Bioinformatics analyses found that the LDL/R→LD homeostasis alteration is critical for therapeutic prognosis. Lastly, using LPC-liposome-cisplatin improved cisplatin sensitivities in gastric cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma cells. In conclusion, this report discovered a LDL/R-reprogrammed transcriptome-lipidome network, by which impulses platinum insensitivity and disease outcome. The drug specific lipidome for liposome manufacture might be an efficienct pharmaceutics strategy for chemoagents.
Significance LDLR reprograms cellular lipidome and transcriptome profiles to determines chemotherapy therapeutic efficacy. The LDLR-reduced LPC abundance disturbs phospholipids homeostasis of Lands cycle in LD, by which attenuates intracellular platinum transportation for DNA-adduct formation. Targeting LDLR-LD-lipidome with LPC-liposome-platinum could boost therapeutic efficacy for insensitivity.
Footnotes
Grant funding: This study was supported in part by grants from the Taiwan Ministry of Science and Technology (MOST104-2628-B-039-001-MY4; MOST106-2221-E-039-011-MY3); National Health Research Institute (NHRI-EX107-10705BI). This study was also supported in part by China Medical University/Hospital (CMU107-S-05; CMU107-TC-02; DMR-108-080; DMR-CELL-17014; DMR-CELL-1806; DMR-108-079).
Conflict of interest statement: All the authors in this work claimed no interests conflict.