title: Leptin-Notch signaling axis is involved in pancreatic cancer progression.
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.
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Harbuzariu
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampoldi
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Daley-Brown
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Candelaria
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Tia L
authors.initials: TL
authors.lastname: Harmon
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Crystal C
authors.initials: CC
authors.lastname: Lipsey
authors.affiliation: Department of Surgery, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Beech
authors.affiliation: Biomedical Informatics Program and Master of Science in Clinical Research Program, Clinical Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Quarshie
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, 30303 USA.
authors.forename: Gabriela Oprea
authors.initials: GO
authors.lastname: Ilies
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA.
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Gonzalez-Perez
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D020738:Leptin; D008024:Ligands; D051880:Receptors, Notch
keywords: Notch; leptin; leptin peptide receptor antagonist LPrA2; pancreatic cancer; pancreatic cancer stem cells