title: Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells.
abstract: Elevation of cAMP inhibits the proliferation and expression of transformed phenotype in several cell types, including breast cancer cells. Leptin has been shown to act as a mitogen/survival factor in many types of cancer cells. In the present work, we have studied the impact of cAMP elevation on leptin-induced proliferation of breast cancer cells. Here we report that treatment of estrogen receptor negative human breast cancer cell line MDA-MB-231 with leptin or cAMP elevating agents has positive and negative effects on cell proliferation, respectively. Surprisingly, we find that leptin strongly potentiates the anti-proliferative action of cAMP elevating agents, by concurring to cell cycle arrest at G1 phase and inducing apoptosis. Pretreatment with the PKA inhibitor KT-5720 completely prevented the anti-proliferative effects induced by the combination between leptin and cAMP elevating agents. The above anti-proliferative effects were paralleled by the decrease of cyclin D1 and A and by the increase of inhibitor p27kip1 cell cycle regulating protein levels. In these conditions we found also a strong decrease of anti-apopotic Bcl2 protein levels. Altogether, our data extend the evidence of adenylate cyclase/cAMP/PKA as a growth suppressor system and of leptin as a growth promoting factor in breast cancer cells. Remarkably, our results suggest that when cAMP levels are increased, leptin drives cells towards apoptosis, and that targeting both cAMP levels and leptin signalling might represent a simple novel way for therapeutic intervention in breast cancer.
authors: Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, Naples, Italy. silvio.naviglio@unina2.it
authors: Silvio
authors: S
authors: Naviglio
authors: Davide
authors: D
authors: Di Gesto
authors: Maria
authors: M
authors: Romano
authors: Annunziata
authors: A
authors: Sorrentino
authors: Fausto
authors: F
authors: Illiano
authors: Luca
authors: L
authors: Sorvillo
authors: Alberto
authors: A
authors: Abbruzzese
authors: Monica
authors: M
authors: Marra
authors: Michele
authors: M
authors: Caraglia
authors: Emilio
authors: E
authors: Chiosi
authors: Annamaria
authors: A
authors: Spina
authors: Gennaro
authors: G
authors: Illiano
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D002227:Carbazoles; D020738:Leptin; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015056:1-Methyl-3-isobutylxanthine