title: Leptin signaling and apoptotic effects in human prostate cancer cell lines.
abstract: BACKGROUND
  Prostate cancer (PCa) progression is often associated with transactivation of the androgen receptor (AR) by endogenous hormones/growth factors. One such factor affecting growth, proliferation, and apoptostis (pro-/anti-) in various cancers is the adipokine leptin. This research studied leptin-induced signaling and apoptosis in androgen sensitive (LNCaP, PC3/AR) and insensitive (PC3, DU145) PCa cell lines.
  
  
  METHODS
  Signaling was studied by immunoblotting in cells overexpressing leptin receptors (LRb), Janus kinase 2 (JAK2), and kinase negative-HER2-YFP cDNAs. Apoptosis was measured by immunoblotting of apoptotic proteins and by Hoechst staining of condensed DNA.
  
  
  RESULTS
  Leptin rapidly induced activation of JAK2, STAT3, and MAPK (ERK1/2) signaling cascades; it may also induce HER2 transactivation via leptin-induced phospho-JAK2. Leptin was then shown to exert clear pro-apoptotic effects, increasing levels of caspase 3, cleavage of its substrate, poly (ADP-ribose) polymerase (PARP) to cleaved PARP(89) , levels of CK 18, a cytoskeletal protein formed during apoptosis, and DNA condensation. Kinase inhibitors indicated that leptin-induced apoptosis is probably mediated by balanced activation of JAK2/STAT3, p38 MAPK, and PKC pathways in PCa cells. A human leptin mutein LRb antagonist, L39A/D40A/F41A, fully inhibited leptin-induced phosphorylation of JAK2, ERK1/2, and Akt/PKB, and partially abrogated effects on apoptotic proteins. In LNCaP and PC3/AR cells, leptin increased AR protein levels in correlation with raised apoptotic markers. Thus, AR may mediate, at least partly, the leptin-induced apoptotic response.
  
  
  CONCLUSIONS
  Leptin can clearly induce apoptosis in human PCa cell lines. These findings could lead to development of new leptin agonists with enhanced pro-apoptotic effects and targeted for use in human PCa.
authors.affiliation: Department of Molecular Pharmacology, The Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Samuel-Mendelsohn
authors.forename: Michal
authors.initials: M
authors.lastname: Inbar
authors.forename: Esther
authors.initials: E
authors.lastname: Weiss-Messer
authors.forename: Leonora
authors.initials: L
authors.lastname: Niv-Spector
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Ronnie J
authors.initials: RJ
authors.lastname: Barkey
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D053538:Keratin-18 / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D053538:Keratin-18; D020738:Leptin; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D054411:Receptors, Leptin; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3