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Primary Culture of Rat Adrenocortical Cells and Assays of Steroidogenic Functions
Published on: March 12, 2019
Lipid synthesis seems to drive proliferation in Men1 mouse adrenals and human adrenocortical cell lines
Adam Edholm1, Su-Chen Li1, Xia Chu1
1Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Abstract:
Adrenocortical carcinoma (ACC) is a devastating disease with few effective treatments. The underlying molecular pathways remain largely unknown. To identify potential pathways and drivers relevant to ACC pathogenesis, we utilized histologically normal adrenals from heterozygous multiple endocrine neoplasia type 1 (Men1) mice to study early adrenocortical tumorigenesis. Employing mass spectrometry-based proteomic profiling, we identified 681 proteins, of which 52 displayed significant differential regulation in the adrenal tissues of heterozygous Men1 mice in comparison with their wild-type counterparts. Among these were fatty acid synthase (FASN) and ATP-citrate lyase (ACLY), two enzymes previously shown to be upregulated in several other types of tumors. To assess the functional impact of ACLY and FASN in ACC, we used H295R cells as the primary model. Cells were treated with SB-204990 (ACLY inhibitor) or C75 (FASN inhibitor), which both showed a dose-dependent antiproliferative effect. Lipidomic analysis revealed a significant reduction in palmitic acid and palmitoleic acid in treated cells compared to controls, supporting a mechanistic link between ACLY/FASN activity and lipid biosynthesis. Finally, data from The Cancer Genome Atlas showed significantly diminished survival outcomes among ACC patients exhibiting high ACLY or FASN expression. These findings underscore the potential importance of exploring the inhibition of lipid synthesis as a promising avenue for further research in the context of human ACC.
Insights
Inhibiting fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) shows promise for treating adrenocortical carcinoma (ACC). Targeting these lipid synthesis enzymes reduced tumor cell proliferation and improved survival outcomes in ACC patients.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with limited therapeutic options.
- The molecular mechanisms driving ACC development are not well understood.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of lipid biosynthesis pathways in adrenocortical tumorigenesis.
- To identify potential therapeutic targets for ACC.
- To evaluate the efficacy of inhibiting fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) in ACC models.
Main Methods:
- Proteomic profiling of mouse adrenal tissues to identify differentially regulated proteins.
- In vitro studies using H295R ACC cells treated with FASN and ACLY inhibitors.
- Lipidomic analysis to assess the impact of enzyme inhibition on lipid biosynthesis.
- Analysis of The Cancer Genome Atlas (TCGA) data to correlate gene expression with patient survival.
Main Results:
- Proteomic analysis revealed differential regulation of 52 proteins, including FASN and ACLY, in early-stage ACC development.
- Inhibition of FASN and ACLY demonstrated a dose-dependent antiproliferative effect on ACC cells.
- ACLY and FASN inhibition significantly reduced key lipid metabolites, confirming their role in lipid biosynthesis.
- High expression of ACLY or FASN correlated with significantly poorer survival outcomes in ACC patients.
Conclusions:
- Fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) are key enzymes in lipid biosynthesis and are implicated in adrenocortical carcinoma (ACC) pathogenesis.
- Inhibiting FASN and ACLY represents a potential therapeutic strategy for ACC.
- Targeting lipid synthesis pathways warrants further investigation for the treatment of human ACC.
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