title: Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma.
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET-focused therapy and implementation of clinical trials for PEL patients.
authors.affiliation: Department of Microbiology, Immunology, & Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA; Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine and.
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA;
authors.forename: Jimena
authors.initials: J
authors.lastname: Trillo-Tinoco
authors.affiliation: Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Yueyu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Medicine and.
authors.forename: Karlie
authors.initials: K
authors.lastname: Bonstaff
authors.affiliation: Department of Medicine and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Doyle
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA;
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.affiliation: Viral Oncology Section, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
authors.forename: Denise
authors.initials: D
authors.lastname: Whitby
authors.affiliation: Department of Medicine and.
authors.forename: Chris
authors.initials: C
authors.lastname: Parsons
authors.affiliation: Department of Medicine and.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Reiss
authors.affiliation: Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA.
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.affiliation: Department of Microbiology, Immunology, & Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA; Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D020552:Comet Assay; D000077547:Crizotinib; D004249:DNA Damage / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors*; D006566:Herpesviridae Infections / Q000150:complications; D019288:Herpesvirus 8, Human; D006801:Humans; D015151:Immunoblotting; D016867:Immunocompromised Host; D054685:Lymphoma, Primary Effusion / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: C066855:HGF protein, human; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met