Gastrin-releasing peptide promotes the growth of HepG2 cells via EGFR-independent ERK1/2 activation

Abstract

Abstract. Gastrin-releasing peptide (GRP) plays an important role in regulating tumor growth and migration. However, little is known about its role in human hepatocellular carcinoma (HCC) cells. This study explored the effect of GRP on the growth of HCC HepG2 cells and the underlying mechanisms. Expression of GRP and its cognate receptor (GRPR) were detected by immunocytochemisty, reverse transcription-PCR and Western blotting and compared between two human HCC cell lines (HepG2 and MHCC97H) and a normal hepatic cell line (HL-7702). The effects of GRP on cell proliferation and signaling pathways were examined by Western blotting, MTT assay and flow cytometry. Both GRP and GRPR were overexpressed in HepG2 and MHCC97H cells. GRP activated MAPK/ERK1/2 in HepG2 cells, leading to enhanced proliferation, reduced apoptosis and accelerated cell cycle progression. The effect of GRP on ERK1/2 was effectively attenuated by the GRPR antagonist PD176252 or MEK inhibitor U0126, but not by the TNF-· protease inhibitor TAPI-1 or the EGFR tyrosine kinase inhibitor PD153035. The effect of GRP on the growth of HepG2 cells was significantly attenuated by PD176252 or U0126. GRP serves as a mitogen for HepG2 and MHCC97H cells. GRP promotes the growth of HepG2 cells through interaction with GRPR co-expressed in tumor cells, and subsequently activates MAPK/ERK1/2 via EGFRindependent mechanisms.

An Insight into GPCR and G-Proteins as Cancer Drivers

“…Activation of GRPR has been shown to increase head and neck cancer cell invasion and proliferation by upregulating EGFR transcription and phosphorylating the downstream MAPK pathway [ 350 , 351 ]. Furthermore, autocrine GRP/GRPR activation can directly activate EGFR pre-ligands via Src-dependent cleavage [ 352 ] and then facilitates phosphorylation of EGFR and activation of MAPK pathway [ 353 ]. These findings imply that GRPR cross-talk with EGFR and GRPR inhibition may affect downstream signaling of EGFR by interfering with intracellular EGFR-activated mediators.…”

In Vivo Biodistribution and Efficacy Evaluation of NeoB, a Radiotracer Targeted to GRPR, in Mice Bearing Gastrointestinal Stromal Tumor

“…GRPR overexpression has been evidenced in a wide spectrum of tumors such as 63 to 100% of prostate, 33 to 72% of breast and 76 to 93% of gastric cancers [4][5][6][7]. Many studies have highlighted that the GRPR pathway is a key actor of cancer progression through increasing proliferation, invasion and migration of cancer cells via autocrine and paracrine pathways [8][9][10].…”

TAPI-1 Exhibits Anti-tumor Efficacy in Human Esophageal Squamous Cell Carcinoma Cells via Suppression of NF-κB Signaling Pathway

“…In recent years, TAPI-1 has been proposed to ameliorate various inflammatory diseases, such as rheumatoid arthritis, kidney injury, and neuroinflammation [ 8 – 10 ]. Additionally, several studies showed that TAPI-1 might display anti-tumor efficacy in pancreatic cancer, breast cancer, and hepatoma [ 11 – 15 ]. However, the effect of TAPI-1 on digestive tract tumors remains to be greatly elucidated.…”