Leptin Induces Proliferation and Notch Expression In Pancreatic Cancer

Pancreatic adenocarcinoma (PA) is an aggressive cancer. It develops in a way that causes almost no detectable symptoms, which leads to a rapid progression and a short survival rate. Researchers have discovered a link between pancreatic cancer (and other cancer types) and obesity. High levels of leptin, an appetite hormone secreted by adipocytes, have been found in obese people. Studies have shown that the absence of leptin in the body or severe leptin resistance can lead to uncontrolled eating and weight gain, hence, its connection to obesity. Consequently, our lab is analyzing the relationship between obesity and leptin and what effects they have on pancreatic cancer progression. We hypothesize that in PA cells, leptin induces proliferation, tumorigenesis, and increased levels of Notch and related molecules. These effects are reversed by our leptin antagonist linked to iron nanoparticles, IONP-LPrA2 (iron oxidized nanoparticles leptin peptide receptor antagonist). We’re mainly focused on 4 cell lines: Panc-1, MiaPaCa-2, and BxPc3 (derived from primary tumors) and AsPc-1 (from a metastatic tumor). Of the primary tumors, Panc-1 and MiaPaCa-2 are more aggressive and BxPc-3 is less aggressive. We expect results validating that leptin will induce proliferation (in Panc-1 and AsPc-1cells by MTT assay), expression of Notch and other molecules (in BxPc3 and MiaPaCa-2 cells by flow cytometry and Western Blot), and tumorsphere formation (in Panc-1). Leptin may also induce Notch expression in Panc-1 tumorspheres. In conclusion, this project will demonstrate the involvement of leptin in PA progression. Leptin\u27s effects will be abrogated by the inhibitor of leptin signaling, IONP-LPrA2

Exploration of Antagonist Efficacy for LPrA2 Like Peptide

Leptin is a small protein hormone that controls satiety and is produced by adipocytes. Obese people have increased levels of circulating leptin. Excessive leptin levels cause a break down in the control of leptin signaling pathways leading to increased angiogenesis, proliferation, cell migration, invasion, and anti-apoptotic events. Obesity and leptin signaling have been linked to cancer progression. Literature shows that LPrA2 is an effective leptin antagonist as it decreases proliferation of breast cancer cells in vitro. This project compares the effectiveness of LPrA2 like compounds in breast cancer cell-line MDA-MB-468 (M-468 BCs). We hypothesize that the new peptide antagonists have shorter sequences than LPrA2 and could be more advantageous inhibitors of leptin signaling in BCs than the original LPrA2. During this study, we first tested toxicity of LPrA2 like peptides in MCF10-A cell-line. Then we tested the effectiveness to inhibit leptin induce S-phase in BCs and compared them to LPrA2. M-468 BCs were treated with various compounds for 48 hours. Cell cycle staging was determined using a cellometer. Our results show that two of the new peptide antagonists were more effective in S-phase inhibition than LPrA2. We also expect that a combination of the new peptide antagonist and chemotherapy drug will inhibit proliferation in vitro. This study could lead to the development of future studies that test the efficacy of C6 and C8 using an in vivo mouse model