ORIGINAL ARTICLE The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt Olorunseun O. Ogunwobi & Ian L. P. Beales Accepted: 8 June 2006 / Published online: 16 August 2006 # Springer-Verlag 2006 Abstract Background and aims Obesity is a major risk factor for the development of colon cancer. Secretion of the hormone leptin from adipocytes is increased in obesity, and serum levels are proportional to body fat mass. Serum leptin levels are an independent risk factor for colon cancer. Leptin receptors are expressed in normal, premalignant and malignant colonic epithelia. We have investigated the effects of leptin on proliferation and apoptosis of colonic cancer cells and the early signalling events involved. Methods Proliferation of HT-29 colon cancer cells in response to leptin was assessed by 3-[4, 5-dimethylthiazol- 2-y-l]-2, 5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was quantified by enzyme-linked immunosorbent assay (ELISA) for intracellular nucleosomes. Signalling pathways involved were determined by using specific inhibitors, quantification of phosphorylated active intermedi- ates and ELISA of active nuclear-translocated transcription factors. Results Leptin stimulated HT-29 cell proliferation and inhibited both serum-starvation and celecoxib-induced apo- ptosis. The proliferative and anti-apoptotic effects of leptin were abolished by inhibition of JAK2 with AG490, phosphatidylinositol 3′-kinase (PI3 kinase) with LY294002 and c-Jun NH 2 -terminal kinase (JNK) with SP600125. Stimulation of HT-29 cells with leptin increased phosphor- ylation of JAK2, Akt and JNK. Activation of JAK2 was upstream of PI3 kinase/Akt but not of JNK. Activation of JAK2 was followed by activation and nuclear translocation of STAT3 and JNK activation led to increased activator protein 1 (AP-1) transcriptional activity. Conclusions Leptin stimulates proliferation and inhibits apoptosis in human colon cancer cells and may be an important factor in the increased incidence of colon cancer in obesity. This effect involves JAK2, PI3 kinase and JNK and activation of the oncogenic transcription factors signal transducer and activator of transcription (STAT)3 and AP-1. Keywords Leptin . Apoptosis . Proliferation . Colon cancer . Janus tyrosine kinase 2 . Akt . c-Jun NH 2 -terminal kinase . Activator protein 1 . STAT3 protein . Celecoxib Abbreviations AP-1 activator protein 1 COX cyclo-oxygenase DMEM Dulbecco’ s modified Eagle medium DMSO dimethyl sulphoxide ELISA enzyme-linked immunosorbent assay FBS foetal bovine serum JAK Janus tyrosine kinase JNK c-Jun NH 2 -terminal kinase MAP mitogen-activated protein kinase MTT 3-[4, 5-dimethylthiazol-2-y-l]-2, 5-diphenyltetrazolium bromide PBS phosphate-buffered saline (pH 7.4) PI3 kinase phosphatidylinositol 3′-kinase STAT signal transducer and activator of transcription Int J Colorectal Dis (2007) 22:401–409 DOI 10.1007/s00384-006-0181-y I. L. P. Beales Gastroenterology Department, Norfolk and Norwich University Hospital, Norwich NR4 7UZ, UK O. O. Ogunwobi : I. L. P. Beales (*) Gastroenterology Research Unit, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, UK e-mail: i.beales@uea.ac.uk