MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells

Tongxin Liu; Qi Li; Quanquan Sun; Yuqin Zhang; Hua Yang; Rong Wang; Longhua Chen; Wei Wang

doi:10.1016/j.bbrc.2014.04.147

MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells

Biochem Biophys Res Commun. 2014 Jun 20;449(1):49-54. doi: 10.1016/j.bbrc.2014.04.147. Epub 2014 May 4.

Authors

Tongxin Liu¹, Qi Li², Quanquan Sun¹, Yuqin Zhang¹, Hua Yang¹, Rong Wang¹, Longhua Chen¹, Wei Wang³

Affiliations

¹ Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China.
² Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China.
³ Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China. Electronic address: wangwei9500@hotmail.com.

PMID: 24802404
DOI: 10.1016/j.bbrc.2014.04.147

Abstract

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC), in subsets of patients, radioresistance is still a major problem in the treatment. In this study, we demonstrated that irradiation induced MET overexpression and activation, and the aberrant MET signal mediated by hepatocyte growth factor (HGF) induced radioresistance. We also found that MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. Further investigation indicated that PHA-665752 suppressed the phosphorylation of the Akt, ERK1/2, and STAT3 proteins in a dose-dependent manner. Our data indicated that the combination of IR with a MET inhibitor, such as PHA-665752, might be a promising therapeutic strategy for NPC.

Keywords: MET inhibitor; Nasopharyngeal carcinoma; Radiosensitivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma
Cell Line, Tumor
Cell Proliferation / drug effects
Chemoradiotherapy / methods*
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Enzyme Activation / radiation effects
Hepatocyte Growth Factor / metabolism*
Humans
Indoles / administration & dosage*
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms / metabolism
Nasopharyngeal Neoplasms / pathology*
Nasopharyngeal Neoplasms / therapy*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Radiation Tolerance
Sulfones / administration & dosage*
Treatment Outcome
Up-Regulation / drug effects
Up-Regulation / radiation effects

Substances

5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
Indoles
Sulfones
Hepatocyte Growth Factor
MET protein, human
Proto-Oncogene Proteins c-met