Transactivation of Epidermal Growth Factor Receptor Is Involved in Leptin-Induced Activation of Janus-Activated Kinase 2 and Extracellular Signal–Regulated Kinase 1/2 in Human Gastric Cancer Cells

Abstract

Leptin is known to act as a growth factor through the Janusactivated kinase (JAK)/signal transducer and activator of transcription signaling pathway as well as the mitogenactivated protein kinase pathway. In this study, we showed a novel signal transduction pathway using two human gastric cancer cell lines, MKN28 and MKN74. Both gastric cancer cells expressed leptin and its receptors (Ob-R) at the protein level. We found that leptin, even at as low as 0.1 ng/mL, induced significant tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Time-course experiments revealed that phosphorylation was maximal after 5 minutes of stimulation and declined thereafter. We also revealed that tyrosine phosphorylation of EGFR induced by leptin was significantly attenuated by two inhibitors, an EGFR tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of EGFR transactivation induced by leptin is dependent on proteolytically released EGFR ligands. Leptin induced JAK2 activation and extracellular signal-regulated kinase (ERK) 1/2 activation in these gastric cancer cells, both of which occurred after the peak of EGFR transactivation. Pretreatment of gastric cancer cells with AG1478 significantly reduced the degree of phosphorylation of both JAK2 and ERK1/2. These findings indicate the involvement of EGFR transactivation in the activation of JAK2 and ERK1/2. Our results reveal that EGFR transactivation is involved in the leptin signaling pathway in gastric cancer cells, which extends the physiologic action of leptin beyond its central effects in the hypothalamus to regulate body weight. (Cancer Res 2005; 65(20): 9159-63)

Identification of Protein Expression Signatures Associated with Helicobacter pylori Infection and Gastric Adenocarcinoma Using Recombinant Antibody Microarrays

“…The latter suggestion was further supported by the up-regulation of vascular endothelial growth factor and angiomotin (Table III), which mediates angiogenesis and has previously been shown to be expressed by carcinomas (26,47,48). Finally sialyl-Lewis X, known to be highly expressed in gastric adenocarcinomas (27), and leptin, a possible neoplastic growth factor (31,32), were also found to be up-regulated in the tumor-associated protein expression profile (Table III).…”

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

“…Leptin induced significant tyrosine phosphorylation of EGFR in MKN28 and MKN74 gastric cancer cell-lines [95]. In the same way, it was found that leptin and IGF-1 cotreatment synergistically transactivated EGFR in MDA-MB-468, MDA-MB-231, and MCF-7 breast cancer cells [96].…”

Triple‑negative breast cancer and its?association with obesity (Review)

“…TNBC is associated with a high frequency of EGFR dysregulation (78,79), and EGFR expression is reported in >50% of TNBC cases. Activation of EGFR provides a potent survival signal in breast cancer, and this activation has been observed in response to a variety of stimulants, including IGF-1 (80) and leptin (81). Lapatinib and erlotinib successfully suppress invasion and migration of TNBC cells induced by combined therapy with leptin and IGF-1.…”