Abstract
Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing disease with high metastatic potential, thus, it requires a robust and renewable source of energy to meet its metabolic demands. High grade PDAC tumors have been shown to lose expression of a potent negative regulator of lipid metabolism, pigment epithelium-derived factor (PEDF). Emerging data support that lipid droplets (LDs) are dynamic organelles in non-adipocytes and they are capable of participating in signaling pathways and as well as providing a source of energy. LDs are composed of a triacylglycerol (TAG) core covered by coat proteins, some of which assist in restricting lipase activity by enzymes such as adipose triglyceride lipase (ATGL). Based on a study of adipose differentiation related protein (ADRP) over expression resulting in lower metalloproteinase (MMP) levels in non-tumor cells, we proposed that ADRP-positive LDs actively participate in cellular invasion. We further postulated that expression of PEDF in PDAC tumors inhibits cellular invasion and reduces lipid energy stores due to an increase in ATGL-mediated TAG catabolism and redistribution of intracytoplasmic LDs. Methods: PANC-1 cells were transfected with the PEDF gene via the pCEP4 vector. PEDF-expressing PANC-1 cells, wild type controls and human pancreatic tumor tissue sections were immunostained for PEDF, ATGL, neutral lipid (Oil-red-O) and the two LD coat proteins, ADRP and tail interacting protein-47 (TIP-47). LD distribution (perinuclear vs. peripheral) was analyzed and matrigel cell invasion assays were performed. To determine the role of LDs in proliferation, TAG synthesis in PANC-1 cells was blocked using a diacylglycerol acyltransferase-1 (DGAT-1) inhibitor. Results: PEDF-expressing PANC-1 cells revealed a 10-fold decrease in cellular invasion and an increase in ATGL expression. Immunostains for LD coat proteins, ADRP and TIP-47, showed a predominantly perinuclear position for LDs in the wild type control cells, whereas, PEDF-expressing cells exhibited more ADRP positive LDs in the peripheral region of the cytoplasm. The LDs located closest to the nucleus had the largest mean diameter. Human PDAC tissue had minimal to no expression of PEDF and exhibited predominantly larger perinuclear LDs with more intense TIP-47 staining as compared to ARDP. Blockade of TAG synthesis with DGAT-1 inhibitor reduced LD size and significantly decreased cellular proliferation. Conclusions: These data suggest that activation of TAG catabolism in PDAC by upregulation of the lipolytic enzyme, ATGL, or blockade of TAG synthesis by a DGAT-1 inhibitor diminishes LD size. Moreover, redistribution of LDs and changes in LD coat protein expression may be one mechanism underlying the anti-invasive function of PEDF in PANC-1 cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1523. doi:1538-7445.AM2012-1523
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