title: STAT3 Inhibition as a Therapeutic Strategy for Chordoma.
abstract: ObjectiveSignal transducer and activator of transcription (STAT) proteins regulate key cellular fate decisions including proliferation and apoptosis. STAT3 overexpression induces tumor growth in multiple neoplasms. STAT3 is constitutively activated in chordoma, a tumor with a high recurrence rate despite maximal surgical and radiation treatment. We hypothesized that a novel small molecule inhibitor of STAT3 (FLLL32) would induce significant cytotoxicity in sacral and clival chordoma cells.MethodsSacral (UCh1) and clival (UM-CHOR-1) chordoma cell lines were grown in culture (the latter derived from primary tumor explants). FLLL32 dosing parameters were optimized using cell viability assays. Antitumor potential of FLLL32 was assessed using clonal proliferation assays. Potential mechanisms underlying observed cytotoxicity were examined using immunofluorescence assays.ResultsFLLL32 induced significant cytotoxicity in UCh1 and UM-CHOR-1 chordoma cells, essentially eliminating all viable cells, correlating with observed downregulation in activated, phosphorylated STAT3 upon administration of FLLL32. Mechanisms underlying the observed cytotoxicity included increased apoptosis and reduced cellular proliferation through inhibition of mitosis.ConclusionAs a monotherapy, FLLL32 induces potent tumor kill in vitro in chordoma cell lines derived from skull base and sacrum. This effect is mediated through inhibition of STAT3 phosphorylation, increased susceptibility to apoptosis, and suppression of cell proliferation.
authors.affiliation: Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington, United States.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Owen
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Albert Einstein College of Medicine, Bronx, New York, United States.
authors.forename: Waleed M
authors.initials: WM
authors.lastname: Abuzeid
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Shawn L
authors.initials: SL
authors.lastname: Hervey-Jumper
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Mikel
authors.initials: M
authors.lastname: Gurrea
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Altshuler
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Prince
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Carey
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Erin L
authors.initials: EL
authors.lastname: McKean
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sullivan
keywords: FLLL32; STAT3; chordoma; sacrum; skull base