title: Coexpression of activated c-Met and death receptor 5 predicts better survival in colorectal carcinoma.
abstract: Dysregulated overexpression of hepatocyte growth factor and its receptor, c-Met, has been reported in various cancers, but its role in colorectal carcinoma (CRC) has not been elucidated. Therefore, we investigated the role of phosphorylated Met (p-Met) in Middle Eastern CRC patient samples and cell lines. The p-Met was overexpressed in 80.8% of CRCs and strongly associated with the expression of p-AKT, DR5, and Ki-67 by immunohistochemistry. Coexpression of p-Met and DR5 was seen in 53.1% of CRC cases and was associated with a less aggressive phenotype, characterized by a histological subtype of adenocarcinomas, well-differentiated tumors, and was an independent prognostic marker for better overall survival. PHA665752, a selective p-Met inhibitor, induced apoptosis in CRC cells via inactivation of c-Met and AKT. PHA665752 treatment also caused increased expression of DR5 via generation of reactive oxygen species, and combination treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and PHA665752 induced significant apoptosis. In vivo, cotreatment of a CRC xenograft with PHA665752 and TRAIL significantly reduced tumor volume and weight. These data demonstrate a significant correlation between p-Met and DR5 in patients with CRC. Furthermore, inhibition of p-Met signaling by PHA665752 in combination with TRAIL significantly inhibited cell growth and induced apoptosis in CRC cell lines, suggesting that this may have significant clinical implications as a therapeutic target in the treatment of CRC.
authors: Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Shahab
authors: S
authors: Uddin
authors: Azhar R
authors: AR
authors: Hussain
authors: Maqbool
authors: M
authors: Ahmed
authors: Nasser
authors: N
authors: Al-Sanea
authors: Alaa
authors: A
authors: Abduljabbar
authors: Luai H
authors: LH
authors: Ashari
authors: Samar
authors: S
authors: Alhomoud
authors: Fouad
authors: F
authors: Al-Dayel
authors: Prashant
authors: P
authors: Bavi
authors: Khawla S
authors: KS
authors: Al-Kuraya
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation / Q000502:physiology; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C480541:5-((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; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013450:Sulfones; D053221:TNF-Related Apoptosis-Inducing Ligand; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met