HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

Abstract

The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a variety of human malignancies. However, its role in epithelial ovarian carcinoma (EOC) has not been clearly elucidated. Therefore, we investigated the role of HGF/c-Met signaling pathway in a large series (156) of Saudi EOC patient samples, a panel of cell lines, and xenografts in a NUDE mouse model. Using immunohistochemistry, c-Met overexpression was found in 27.2% Middle Eastern EOC samples and was associated with an advanced tumor stage (P ¼ 0.0187). c-Met overexpression was also associated with antiapoptotic markers X-chromosome-linked inhibitors of apoptosis (XIAP) (P ¼ 0.0008) and Bcl-XL (P ¼ 0.0493) expression. Treatment of EOC cell lines with PHA665752 causes a dose-dependent inhibition of cell viability and induction of apoptosis. Furthermore, PHA665752 treatment causes dephosphorylation of AKT and downregulation of antiapoptotic proteins XIAP and Bcl-XL. In addition, PHA665752-induced apoptosis occurs through activation of Bax-mediated release of cytochrome c and activation of caspases. Finally, co-treatment of EOC with PHA665752 and cisplatin causes augmented effect on apoptosis of EOC cells and resulted in synergistic inhibition of EOC xenograft tumor growth in NUDE mice. These results indicate that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of EOC.

Coexpression of Activated c-Met and Death Receptor 5 Predicts Better Survival in Colorectal Carcinoma

“…Previously, p-Met activation secondary to HGF stimulation required low doses of PHA665752 40 ; however, when p-Met is constitutively activated, higher doses of PHA665752 are required. 41,42 We have also previously shown that treatment with PHA665752 at doses of 1 and 5 mol/L does not affect the phosphorylation status of other proteins, such as pLyn, p-Stat3, p-Jak2, and p-SRC, in epithelial ovarian cancer. 41 Therefore, we selected working doses of 1 and 5 mol/L of PHA665752 for our in vitro experiments.…”

“…41,42 We have also previously shown that treatment with PHA665752 at doses of 1 and 5 mol/L does not affect the phosphorylation status of other proteins, such as pLyn, p-Stat3, p-Jak2, and p-SRC, in epithelial ovarian cancer. 41 Therefore, we selected working doses of 1 and 5 mol/L of PHA665752 for our in vitro experiments. Next, we treated CRC cell lines with 1 and 5 mol/L of PHA665752, and cell cycle fractions were analyzed by flow cytometry.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…In recent years, mis-regulation of the HGF/cMET pathway has been investigated in ovarian cancer, and high expression of cMET has been identified in subsets of all four major histotypes of EOC (high grade serous, clear cell, mucinous, and endometrioid [22][23][24][25][26][27][28][29]). It must be noted, however, that the outcome from this over-expression remains unclear.…”

“…For example, recent IHC studies performed on gastric tumour samples have reported cMET over-expression in 4-63% of cases [72][73][74][75][76][77] and various studies performed in ovarian cancer estimate high expression of cMET to be present in 11-68 % of cases [30,22,23,26,25] (Table 1). The majority of the estimates above come from IHC studies, using a number of different antibodies, but no consensus on scoring criteria yet exists, nor whether cytoplasmic or membranous staining for cMET is important.…”

“…However, surprisingly, no biomarkers were used, nor were analyses performed post-hoc on patients responding to treatment. With current estimates of high cMET expression occurring in 11-68% of ovarian cancer cases (see Table 1) [30,22,23,26,25], it is possible that as few as 3 patients enrolled within the study were in a position to benefit from receiving the anti-HGF antibody, and that as many as 29 patients potentially to do worse upon receiving the therapy.…”