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Endocr Relat Cancer. 2019 Dec 1. pii: ERC-19-0095.R3. doi: 10.1530/ERC-19-0095. [Epub ahead of print]

LDLR-mediated lipidome-transcriptome reprogramming in cisplatin insensitivity.

Author information

1
W Chang, Sex Hormone Research Center, Dept of OBS and GYN, China Medical University/Hospital, Taichung City, Taiwan.
2
H Wang, Sex Hormone Research Center, China Medical University, Taichung, Taiwan.
3
W Cheng, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
4
J Yang, Sex Hormone Research Center, China Medical University/Hospital, Taichung City, Taiwan.
5
W Chung, Sex Hormone Research Center, Dept of OBS and GYN, China Medical University/Hospital, Taichung City, Taiwan.
6
Y Ho, Sex Hormone Research Center, China Medical University/Hospital, Taichung City, Taiwan.
7
L Chen, Sex Hormone Research Center, Dept of OBS and GYN, China Medical University/Hospital, Taichung City, Taiwan.
8
Y Hung, Sex Hormone Research Center, Dept of OBS and GYN, China Medical University/Hospital, Taichung City, Taiwan.
9
W Ma, Graduate Institution of Biomedical Sciences, China Medical University, Taichung, Taiwan.

Abstract

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptors-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularity, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients disease prognosis. In vitro and in vivo add-in/silencing LDLR were introduced to determines cisplatin sensitivity and cancer growth. Result revealed knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR-->LPC (Lyso-phosphatidylcholine)-->FAM83B (phospholipase-related)-->FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR-->LPC-->FAM83B-->FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs.

PMID:
31815680
DOI:
10.1530/ERC-19-0095

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