Leptin-Notch signaling axis is involved in pancreatic cancer progression.

// Adriana Harbuzariu 1 , Antonio Rampoldi 1 , Danielle S Daley-Brown 1 , Pierre Candelaria 1 , Tia L Harmon 1 , Crystal C Lipsey 1 , Derrick J Beech 2 , Alexander Quarshie 3 , Gabriela Oprea Ilies 4 , Ruben R Gonzalez-Perez 1 1 Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA 2 Department of Surgery, Morehouse School of Medicine, Atlanta, GA, 30310 USA 3 Biomedical Informatics Program and Master of Science in Clinical Research Program, Clinical Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA 4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, 30303 USA Correspondence to: Ruben R Gonzalez-Perez, email: rgonzalez@msm.edu Keywords: leptin, Notch, pancreatic cancer, pancreatic cancer stem cells, leptin peptide receptor antagonist LPrA2 Received: September 12, 2016      Accepted: December 07, 2016      Published: December 15, 2016 ABSTRACT Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.