Leptin-Induce Proliferation Mediated by JAK/STAT and MAPK Activation in Acute Myelogenous Leukemia Cells.

Abstract

Leptin, secreted as a product of the ob gene that is mainly produced by adipose tissue, has been involved in the regulation of energy metabolism. Recently, leptin has been suggested to stimulate normal cells as well as various cancer cells including acute myelogenous leukemia (AML). However, the molecular mechanism of leptin as a proliferative effector is not poorly understood in AML. In the present study, we show that leptin-induced cellular proliferation is mediated by JAK/STAT and MAPK activation in AML. Expression of the long form (Ob-Rb) and the short form (Ob-Ra) of leptin receptor (Ob-R) was observed in 10 AML cell lines examined, and up-regulated by treatment of leptin. Leptin induced the proliferation of HEL, which was shown to express the highest Ob-R among AML cell lines, in a dose-dependent manner. Treatment with 100ng/ml of leptin enhanced the expression of Janus kinase 2 (JAK2) phosphorylation, signal transducer and activator of transcription (STAT)-3 phosphorylation and mitogen-activated protein kinases (MAPKs) in HEL. Blocking of STAT3 phosphorylation with a specific inhibitor, AG490 (50 μM), significantly reduced leptin-induced ERK1/2 phosphorylation and cellular proliferation of HEL, whereas blocking of ERK1/2 activation by a specific ERK1/2 kinase inhibitor, PD98059 (25 μM), did not affect the STAT3 phosphorylation and leptin-induced proliferation in HEL. Furthermore, knockdown of Ob-R expression with small interfering RNA (siRNA) reduced leptin-induced proliferation of HEL, and also significantly attenuated leptin-induced STAT3 and ERK1/2 activation. This results provides that leptin promotes AML cell growth by activating JAK/STAT3 and MAPK, although not directly dependent on ERK. Blocking as direct receptor level could be a rational therapeutic strategy of AML.