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Biosynthesis of acyl‐CoAs sustains prostate cancer progression
Author(s) -
Cai Houjian,
Ma Yongjie
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.811.1
Subject(s) - prostate cancer , cancer , carnitine , prostate , fatty acid , biology , fatty acid synthesis , tumor progression , biochemistry , lipid metabolism , cancer research , chemistry , medicine , gene
Objective of the study Fatty acid metabolism is essential for the biogenesis of cellular components and ATP production to sustain proliferation of cancer cells. Bioconversion of exogenous or de novo synthesized fatty acids to their corresponding fatty acyl‐CoAs, which is required for the fatty acids to participate in metabolic processes, is catalyzed by long chain fatty acyl‐CoA synthetases (ACSLs). However, the influence of individual ACSL isoforms on the progression of prostate cancer remains unknown. The goal of this study is 1) to analyze how ACSLs regulates the biosynthesis of acyl‐CoAs, thereby prostate cancer progression. Statement of Methods Lentivirus carrying shRNA of ACSL1 was constructed and produced in house. Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR) were measured by Seahorse. The amount of protein was evaluated by immunoblotting. The amount of acyl‐CoAs was analyzed by LC‐MS/MS. The amount of triglyceride and neutral lipid were measured by gas Chromatography and Oil red O staining, respectively. TCGA database was used for analysis of ACSL1 expression levels in different stages of prostate cancer. Additionally, inhibition of cell proliferation, migration, invasion assays and cell cycle analysis were analyzed in numerous cancer cells. Prostate xenograft tumor models were applied for in vivo studies. Prostate tumor tissue array was utilized for the analysis of ACSL1 expression. Summary of the results In this study, the correlation of ACSL expression levels and the amount of intracellular acyl‐CoAs was systematically analyzed. We demonstrate that expression levels of ACSL1 were significantly associated with the levels of a variety of acyl‐CoAs, and were elevated in human prostate tumors. ACSL1 increased the biosynthesis of fatty acyl‐CoAs including C16:0−, C18:0−, C18:1− and C18:2‐CoA, triglycerides and lipid accumulation in cancer cells. In addition, ACSL1 modulated mitochondrial respiration through regulation of carnitine palmitoyltransferase 1A (CPT1A) activity. Knockdown of ACSL1 expression inhibited the cell cycle, and suppressed the proliferation and migration of prostate cancer cells in vitro, and growth of prostate xenograft tumors in vivo. Conclusion Our study demonstrates ACSL1 as playing a role in prostate tumor progression. Our results provide a therapeutic strategy of targeting fatty acid metabolism for the treatment of prostate cancer. Support or Funding Information NIH (R01CA172495) and DOD (W81XWH‐15‐1‐0507)