Abstract
BackgroundNeoplastic cells proliferate rapidly and obtain requisite building blocks by reprogramming metabolic pathways that favor growth. Previously, we observed that prostate cancer cells uptake and store lipids in the form of lipid droplets, providing building blocks for membrane synthesis, to facilitate proliferation and growth. Mechanisms of lipid uptake, lipid droplet dynamics and their contribution to cancer growth have yet to be defined. This work is focused on elucidating the prostate cancer-specific modifications in lipid storage pathways so that these modified gene products can be identified and therapeutically targeted.MethodsTo identify genes that promote lipid droplet formation and storage, the expression profiles of candidate genes were assessed and compared between peripheral blood mononuclear cells and prostate cancer cells. Subsequently, differentially expressed genes were inhibited and growth assays performed to elucidate their role in the growth of the cancer cells. Cell cycle, apoptosis and autophagy assays were performed to ascertain the mechanism of growth inhibition.ResultsOur results indicate that DGAT1, ABHD5, ACAT1 and ATGL are overexpressed in prostate cancer cells compared to PBMCs and of these overexpressed genes, DGAT1 and ABHD5 aid in the growth of the prostate cancer cells. Blocking the expression of both DGAT1 and ABHD5 results in inhibition of growth, cell cycle block and cell death. DGAT1 siRNA treatment inhibits lipid droplet formation and leads to autophagy where as ABHD5 siRNA treatment promotes accumulation of lipid droplets and leads to apoptosis. Both the siRNA treatments reduce AMPK phosphorylation, a key regulator of lipid metabolism. While DGAT1 siRNA reduces phosphorylation of ACC, the rate limiting enzyme in de novo fat synthesis and triggers phosphorylation of raptor and ULK-1 inducing autophagy and cell death, ABHD5 siRNA decreases P70S6 phosphorylation, leading to PARP cleavage, apoptosis and cell death. Interestingly, DGAT-1 is involved in the synthesis of triacylglycerol where as ABHD5 is a hydrolase and participates in the fatty acid oxidation process, yet inhibition of both enzymes similarly promotes prostate cancer cell death.ConclusionInhibition of either DGAT1 or ABHD5 leads to prostate cancer cell death. Both DGAT1 and ABHD5 can be selectively targeted to block prostate cancer cell growth.
Highlights
Neoplastic cells proliferate rapidly and obtain requisite building blocks by reprogramming metabolic pathways that favor growth
We screened and compared the expression pattern of 10 genes involved in lipid droplet formation and processing in LNCaP and peripheral blood mononuclear cells (PBMCs) incubated with and without plasma: (ABHD5, ACAT1, adipose triglyceride lipase (ATGL), Diglyceride acyltransferase (DGAT1)/2, FSP27, hormone sensitive lipase (HSL), OXPAT, perilipin and tail interacting protein 47 (TIP47)) (Fig. 1a)
Four genes Alpha/beta- hydrolase domain containing protein 5 (ABHD5), ACAT1, ATGL and DGAT1 were overexpressed in LNCaP as compared to PBMCs
Summary
Neoplastic cells proliferate rapidly and obtain requisite building blocks by reprogramming metabolic pathways that favor growth. We observed that prostate cancer cells uptake and store lipids in the form of lipid droplets, providing building blocks for membrane synthesis, to facilitate proliferation and growth. In several cancers dysregulated fatty acid (FA) synthesis, storage, uptake transport and degradation are associated with disease outcome. Some of these cancer cells are known to upregulate FA synthesis which in turn supports rapid proliferation and decreased drug sensitivity [12, 13, 15, 16]. Cancer cells tend to alter FA synthesis by increasing production of fatty acid precursors glutamine and citrate; alternately they uptake extracellular FA for use as building blocks, energy production and storage [17,18,19]. Knockdown studies on FA synthesis genes show poor prognosis and decreased overall survival in several cancers including prostate [13, 18, 20, 21] FA synthesis genes have been implicated as therapeutic targets [15]
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