This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Russo, V. C. Articles by Werther, G. A. Search for Related Content PubMed PubMed Citation Articles by Russo, V. C. Articles by Werther, G. A.

Antiapoptotic Effects of Leptin in Human Neuroblastoma Cells

Centre for Hormone Research, Murdoch Childrens Research Institute, Department of Paediatrics University of Melbourne, Royal Children’s Hospital, Parkville 3052, Victoria, Australia

Address all correspondence and requests for reprints to: Vincenzo C. Russo, Ph.D., Centre for Hormone Research, Murdoch Childrens Research Institute, Parkville 3052, Victoria, Australia. E-mail: vince.russo{at}mcri.edu.au.

Many factors regulate nervous system development, including complex cross-talk between local neuroendocrine systems. The adipocyte-secreted hormone leptin, mainly known for its key roles in nutrition and reproductive balance, may also be involved in neuroanatomical organization, myelination processes, and neuronal/glia maturation. SK-N-SH-SY5Y neuroblastoma cells were employed as an in vitro model of human neuronal cells to determine whether leptin exerts neuroprotective activities. We show that SH-SY5Y cells express leptin, the long and short isoforms of the leptin receptor (ObRl, ObRs). In SH-SY5Y cells, leptin induced signal transducer and activator of transcription (STAT)-3 phosphorylation and suppressor of cytokine signaling-3 mRNA expression. Leptin dose-dependently increased cell number (up to 200% at 1 µM by 48 h, P < 0.01), and at 24–48 h, leptin at 100 nM increased SH-SY5Y cell number by 30–50%, respectively. SH-SY5Y cell viability was reduced in serum-free conditions at 24 h, and addition of leptin at 100 nM significantly reduced apoptosis by approximately 20% (P < 0.001). Leptin’s antiapoptotic activity required Janus kinase/STAT, MAPK, and phosphatidylinositol-3-kinase activation because the antiapoptotic effects of leptin were abolished, and caspase-3 immunoreactivity increased in the presence of the specific blockers AG490, U0126, or LY294002. Gene array demonstrated that leptin inhibits apoptosis via potent down-regulation of caspase-10 and TNF-related apoptosis-inducing ligand. Our data thus demonstrate, for the first time, that leptin stimulates, in a time- and dose-dependent manner, neuroblastoma cell proliferation and that the underlying mechanisms involve suppression of apoptosis via the Janus kinase-STAT, phosphatidylinositol-3 kinase, and MAPK pathways that culminate altogether in the down-regulation of the apoptotic factors caspase-10 and TNF-related apoptosis-inducing ligand.

This article has been cited by other articles:

				P. Poomthavorn, S. H X Wong, S. Higgins, G. A Werther, and V. C Russo Activation of a prometastatic gene expression program in hypoxic neuroblastoma cells Endocr. Relat. Cancer, September 1, 2009; 16(3): 991 - 1004. [Abstract] [Full Text] [PDF]

				I. L P Beales and O. O Ogunwobi Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation J. Mol. Endocrinol., April 1, 2009; 42(4): 305 - 318. [Abstract] [Full Text] [PDF]

				Y. Benomar, F. Berthou, C.-M. Vacher, V. Bailleux, A. Gertler, J. Djiane, and M. Taouis Leptin But Not Ciliary Neurotrophic Factor (CNTF) Induces Phosphotyrosine Phosphatase-1B Expression in Human Neuronal Cells (SH-SY5Y): Putative Explanation of CNTF Efficacy in Leptin-Resistant State Endocrinology, March 1, 2009; 150(3): 1182 - 1191. [Abstract] [Full Text] [PDF]

				F. Zhang, S. Wang, A. P. Signore, and J. Chen Neuroprotective Effects of Leptin Against Ischemic Injury Induced by Oxygen-Glucose Deprivation and Transient Cerebral Ischemia Stroke, August 1, 2007; 38(8): 2329 - 2336. [Abstract] [Full Text] [PDF]

				Y.-P. Lu, B. Nolan, Y.-R. Lou, Q.-Y. Peng, G. C. Wagner, and A. H. Conney Voluntary exercise together with oral caffeine markedly stimulates UVB light-induced apoptosis and decreases tissue fat in SKH-1 mice PNAS, July 31, 2007; 104(31): 12936 - 12941. [Abstract] [Full Text] [PDF]

				C. Chen, Y.-C. Chang, C.-L. Liu, T.-P. Liu, K.-J. Chang, and I.-C. Guo Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway Endocr. Relat. Cancer, June 1, 2007; 14(2): 513 - 529. [Abstract] [Full Text] [PDF]

				M. P. Magarinos, V. Sanchez-Margalet, M. Kotler, J. C. Calvo, and C. L. Varone Leptin Promotes Cell Proliferation and Survival of Trophoblastic Cells Biol Reprod, February 1, 2007; 76(2): 203 - 210. [Abstract] [Full Text] [PDF]

				C. D. Morrison, C. L. White, Z. Wang, S.-Y. Lee, D. S. Lawrence, W. T. Cefalu, Z.-Y. Zhang, and T. W. Gettys Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age Endocrinology, January 1, 2007; 148(1): 433 - 440. [Abstract] [Full Text] [PDF]

				H. Cui, F. Cai, and D. D. Belsham Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1 FASEB J, December 1, 2006; 20(14): 2654 - 2656. [Abstract] [Full Text] [PDF]

				E. Mansour, F. G. Pereira, E. P. Araujo, M. E. C. Amaral, J. Morari, N. R. Ferraroni, D. S. Ferreira, I. Lorand-Metze, and L. A. Velloso Leptin Inhibits Apoptosis in Thymus through a Janus Kinase-2-Independent, Insulin Receptor Substrate-1/Phosphatidylinositol-3 Kinase-Dependent Pathway Endocrinology, November 1, 2006; 147(11): 5470 - 5479. [Abstract] [Full Text] [PDF]

				O. Ogunwobi, G. Mutungi, and I. L. P. Beales Leptin Stimulates Proliferation and Inhibits Apoptosis in Barrett's Esophageal Adenocarcinoma Cells by Cyclooxygenase-2-Dependent, Prostaglandin-E2-Mediated Transactivation of the Epidermal Growth Factor Receptor and c-Jun NH2-Terminal Kinase Activation Endocrinology, September 1, 2006; 147(9): 4505 - 4516. [Abstract] [Full Text] [PDF]

				V. C. Russo, B. S. Schutt, E. Andaloro, S. I. Ymer, A. Hoeflich, M. B. Ranke, L. A. Bach, and G. A. Werther Insulin-Like Growth Factor Binding Protein-2 Binding to Extracellular Matrix Plays a Critical Role in Neuroblastoma Cell Proliferation, Migration, and Invasion Endocrinology, October 1, 2005; 146(10): 4445 - 4455. [Abstract] [Full Text] [PDF]

				A. Yadav, A. Kalita, S. Dhillon, and K. Banerjee JAK/STAT3 Pathway Is Involved in Survival of Neurons in Response to Insulin-like Growth Factor and Negatively Regulated by Suppressor of Cytokine Signaling-3 J. Biol. Chem., September 9, 2005; 280(36): 31830 - 31840. [Abstract] [Full Text] [PDF]

				U. Meissner, R. Spranger, M. Lehner, I. Allabauer, W. Rascher, and J. Dotsch Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis Eur. J. Endocrinol., September 1, 2005; 153(3): 455 - 461. [Abstract] [Full Text] [PDF]

				M. Lappas, M. Permezel, and G. E. Rice Leptin and Adiponectin Stimulate the Release of Proinflammatory Cytokines and Prostaglandins from Human Placenta and Maternal Adipose Tissue via Nuclear Factor-{kappa}B, Peroxisomal Proliferator-Activated Receptor-{gamma} and Extracellularly Regulated Kinase 1/2 Endocrinology, August 1, 2005; 146(8): 3334 - 3342. [Abstract] [Full Text] [PDF]

				A. Bruno, S. Conus, I. Schmid, and H.-U. Simon Apoptotic Pathways Are Inhibited by Leptin Receptor Activation in Neutrophils J. Immunol., June 15, 2005; 174(12): 8090 - 8096. [Abstract] [Full Text] [PDF]

				S. M. Poulose, E. D. Harris, and B. S. Patil Citrus Limonoids Induce Apoptosis in Human Neuroblastoma Cells and Have Radical Scavenging Activity J. Nutr., April 1, 2005; 135(4): 870 - 877. [Abstract] [Full Text] [PDF]