Identification of CETP as a molecular target for estrogen positive breast cancer cell death by cholesterol depleting agents
| Autor: | Mandeep Kaur, Luke Esau, Sunil Sagar, Dhinoth Kumar Bangarusamy |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class medicine.medical_treatment Intrinsic apoptosis Cancer Estrogen receptor Biology Pharmacology medicine.disease 03 medical and health sciences Steroid hormone 030104 developmental biology Estrogen Apoptosis Cholesterylester transfer protein Genetics medicine biology.protein lipids (amino acids peptides and proteins) Tamoxifen medicine.drug |
| Zdroj: | Genes & Cancer. 7:309-322 |
| ISSN: | 1947-6027 |
| DOI: | 10.18632/genesandcancer.122 |
| Popis: | Cholesterol and its metabolites act as steroid hormone precursors, which promote estrogen receptor positive (ER+) breast cancer (BC) progression. Development of cholesterol targeting anticancer drugs has been hindered due to the lack of knowledge of viable molecular targets. Till now, Cholesteryl ester transfer protein (CETP) has been envisaged as a feasible molecular target in atherosclerosis, but for the first time, we show that CETP contributes to BC cell survival when challenged with cholesterol depleting agents. We show that MCF-7 CETP knockout BC cells pose less resistance towards cytotoxic compounds (Tamoxifen and Acetyl Plumbagin (AP)), and were more susceptible to intrinsic apoptosis. Analysis of differentially expressed genes using Ingenuity Pathway Analysis (IPA), in vivo tumor inhibition, and in vitro phenotypic responses to AP revealed a unique CETP-centric cholesterol pathway involved in sensitizing ER+ BC cells to intrinsic mitochondrial apoptosis. Furthermore, analysis of cell line, tissue and patient data available in publicly available databases linked elevated CETP expression to cancer, cancer relapse and overall poor survival. Overall, our findings highlight CETP as a pharmacologically relevant and unexploited cellular target in BC. The work also highlights AP as a promising chemical entity for preclinical investigations as a cholesterol depleting anticancer therapeutic agent. |
| Databáze: | OpenAIRE |
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