title: Interactions between PTEN and the c-Met pathway in glioblastoma and implications for therapy.
abstract: The tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is often mutated in glioblastoma. Because PTEN can interact with c-Met-dependent signaling, we studied the effects of PTEN on c-Met-induced malignancy and associated molecular events and assessed the potential therapeutic value of combining PTEN restoration approaches with HGF/c-Met inhibition. We studied the effects of c-Met activation on cell proliferation, cell cycle progression, cell migration, cell invasion, and associated molecular events in the settings of restored or inhibited PTEN expression in glioblastoma cells. We also assessed the experimental therapeutic effects of combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition. PTEN significantly inhibited HGF-induced proliferation, cell cycle progression, migration, and invasion of glioblastoma cells. PTEN attenuated HGF-induced changes of signal transduction proteins Akt, GSK-3, JNK, and mTOR as well as cell cycle regulatory proteins p27, cyclin E, and E2F-1. Combining PTEN restoration to PTEN-null glioblastoma cells with c-Met and HGF inhibition additively inhibited tumor cell proliferation and cell cycle progression. Similarly, combining a monoclonal anti-HGF antibody (L2G7) with the mTOR inhibitor rapamycin had additive inhibitory effects on glioblastoma cell proliferation. Systemic in vivo delivery of L2G7 and PTEN restoration as well as systemic in vivo deliveries of L2G7 and rapamycin additively inhibited intracranial glioma xenograft growth. These preclinical studies show for the first time that PTEN loss amplifies c-Met-induced glioblastoma malignancy and suggest that combining anti-HGF/c-Met approaches with PTEN restoration or mTOR inhibition is worth testing in a clinical setting.
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Li
authors.forename: Fadila
authors.initials: F
authors.lastname: Guessous
authors.forename: Charles
authors.initials: C
authors.lastname: DiPierro
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tucker
authors.initials: T
authors.lastname: Mudrick
authors.forename: Lauren
authors.initials: L
authors.lastname: Fuller
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Johnson
authors.forename: Lukasz
authors.initials: L
authors.lastname: Marcinkiewicz
authors.forename: Matthew
authors.initials: M
authors.lastname: Engelhardt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kefas
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human