Low-Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity
| Autor: | Wen Lung Ma, Yen-Pin Ho, Yao Ching Hung, Lumin Chen, Hsiao-Ching Wang, Wei Chun Chang, Juan-Cheng Yang, Wei-Chung Cheng, Wei-Min Chung |
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| Rok vydání: | 2018 |
| Předmět: |
Cisplatin
Microarray endocrine system diseases business.industry Chemistry Cancer Lipidome medicine.disease female genital diseases and pregnancy complications Transcriptome In vivo Lipid droplet LDL receptor Cancer research medicine Gene silencing Adenocarcinoma lipids (amino acids peptides and proteins) business Receptor medicine.drug |
| DOI: | 10.1101/502401 |
| Popis: | Background: Platinum-based therapy remains the cornerstone for cancer therapy; however, efficacy varies. The role of tumor macroenvironmental lipid entry via lipoprotein receptors has been reported. Yet, the roles and mechanism of low-density lipoprotein receptor (LDLR) in chemo-sensitivities are in large. Method: Patient study: Single cohort or public database cDNA microarray to associate LDLR expressions of epithelial ovarian carcinomas (EOCs) with disease prognosis. Laboratory study: In vitro and in vivo add-in/silencing LDLR were introduced to determines cisplatin sensitivity. Transcriptome-Lipidome Trans-omics and bioinformatic analyses to model molecular mechanism. Translation study: LDLR-lipidome was implemented to formulate efficacy boosting liposome. Findings: The LDLR expression is associate with platin-based chemotherapy patients prognosis. The LDLR abundance in EOC subtypes is associated with cisplatin sensitivity. Knocked-down or overexpressed LDLR in EOC could reversed the chemosensitivity pattern in vitro and in vivo. 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 facilitated DNA-adduct formation via lipid droplets (LDs) delivery. Bioinformatics analyses found that the LDL/R-route alters LD homeostasis, which is critical for therapeutic prognosis. Lastly, using LPCliposome could improve multiple cancer types of cisplatin insensitive cells. Interpretation: The LDL/R-route as tumor macroenvironmental lipid entry which impulses platinum insensitivity and disease outcome. The drug specific lipidome for liposome manufacture might be an efficienct pharmaceutics strategy for chemoagents. Funding Statement: This study was supported by 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); and China Medical University/Hospital (CMU107-S-05; CMU107-TC-02; DMR-108-080; DMR-CELL-17014; DMR-CELL-1806; DMR-108-079). Declaration of Interests: All the authors in this work claimed no interests conflict. Ethics Approval Statement: Access to the tissue samples was approved by the Internal Review Board of China Medical University Hospital (DMR101-IRB2-276; and CMU105-REC3-122(CR1)). All the animal studies were performed under the supervision and guidelines of the China Medical University Animal Care and Use Committee (#CMOIACUC-2018-089). |
| Databáze: | OpenAIRE |
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