Small molecule inhibitor of c-Met (PHA665752) suppresses the growth of ovarian cancer cells and reverses cisplatin resistance

Enze Li, Zheng Hu, Yi Sun, Qi Zhou, Bin Yang, Zhiguo Zhang, Wenwu Cao

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

c-Met as a tyrosine-kinase receptor plays a major role in tumorigenesis, invasion, and metastatic spread of human tumors, including ovarian cancer. Expressing high levels of c-Met proteins is often associated with resistance to chemotherapy and an adverse prognosis. In this study, we have determined the effect of PHA665752, a small molecule inhibitor of c-Met proteins, with and without cisplatin and the role of c-Met in several ovarian cancer cell lines having high c-Met expression. The methyl thiazolyl tetrazolium (MTT) assay was used to detect cell proliferation, and apoptosis was evaluated by flow cytometry. Western blotting was carried out to determine protein expression levels. Gene silencing was used to detect the influence of c-Met gene silence on the resistance to cisplatin. Compared to more sensitive ovarian cancer cell lines SKOV3 and 3AO, we found that the expression of c-Met was significantly increased in SKOV3DDP, OVCAR3, and OV-90 ovarian cancer cell lines, which were resistant to cisplatin. Our data indicated that cisplatin sustained activated phosphor-Met in SKOV3DDP, OVCAR3, and OV-90 cell lines. We also observed a significant transient activation of c-Met phosphorylation in SKOV3 and 3AO cells. Treatment with PHA665752 inhibited c-Met expression inhibited cell growth, induced apoptosis, and enhanced cisplatin-induced proliferation inhibition and apoptosis in c-Met over-expressed cell lines. In addition, blocking c-Met expression with small interfering RNA (siRNA) overcame the resistance of cancer cells to cisplatin. Thus, blocking c-Met expression presents a promising therapeutic approach for ovarian cancer.

Original languageEnglish (US)
Pages (from-to)7843-7852
Number of pages10
JournalTumor Biology
Volume37
Issue number6
DOIs
StatePublished - Jun 1 2016

All Science Journal Classification (ASJC) codes

  • Cancer Research

Fingerprint Dive into the research topics of 'Small molecule inhibitor of c-Met (PHA665752) suppresses the growth of ovarian cancer cells and reverses cisplatin resistance'. Together they form a unique fingerprint.

Cite this