title: The Novel Small Molecule Inhibitor, OSU-T315, Suppresses Vestibular Schwannoma and Meningioma Growth by Inhibiting PDK2 Function in the AKT Pathway Activation.
abstract: Activation of PKB/AKT signaling, which requires PDK1 and PDK2 function, drives Vestibular Schwannoma (VS) and meningioma growth. PDK2 function is defined as a molecule that phosphorylates AKT-Ser473. Integrin-Linked Kinase (ILK) functions as PDK2 in PKB/AKT activation in many cancers; therefore, we hypothesized that OSU-T315, a small molecule ILK inhibitor, will inhibit the ILK-PDK2 function in PKB/AKT signaling activation in VS and meningioma cell growth. OSU-T315 decreased cell viability at IC50 < 2μM in VS (HEI193) and meningioma (Ben-Men-1) cell lines, in primary cells at < 3.5μM, while in normal primary Schwann cells at 7.1μM. OSU-T315 inhibits AKT signaling by decreasing phosphorylation at AKT-Ser473, AKT-Thr308, ILK-Ser246 and ILK-Thr173. In addition, OSU-T315 affected the phosphorylation or expression levels of AKT downstream proliferation effectors as well as autophagy markers. Flow cytometry shows that OSU-T315 increased the percentage of cells arrested at G2/M for both, HEI193 (39.99%) and Ben-Men-1 (26.96%) cells, compared to controls (21.54%, 8.47%). Two hours of OSU-T315 treatment increased cell death in both cell lines (34.3%, 9.1%) versus untreated (12.1%, 8.1%). Though longer exposure increased cell death in Ben-Men-1, TUNEL assays showed that OSU-T315 does not induce apoptosis. OSU-T315 was primarily cytotoxic for HEI193 and Ben-Men-1 inducing a dysregulated autophagy. Our studies suggest that OSU-T315 has translational potential as a chemotherapeutic agent against VS and meningioma.
authors.affiliation: Ear Institute, University of Arizona, USA; Department of Otolaryngology, University of Arizona, USA; Arizona Cancer Center, University of Arizona, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Mercado-Pimentel
authors.affiliation: Ear Institute, University of Arizona, USA; Department of Otolaryngology, University of Arizona, USA.
authors.forename: S
authors.initials: S
authors.lastname: Igarashi
authors.affiliation: Ear Institute, University of Arizona, USA; Department of Otolaryngology, University of Arizona, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Dunn
authors.affiliation: Ear Institute, University of Arizona, USA; Department of Otolaryngology, University of Arizona, USA.
authors.forename: M
authors.initials: M
authors.lastname: Behbahani
authors.affiliation: Ear Institute, University of Arizona, USA; Department of Otolaryngology, University of Arizona, USA.
authors.forename: C
authors.initials: C
authors.lastname: Miller
authors.affiliation: Ear Institute, University of Arizona, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Read
authors.affiliation: Ear Institute, University of Arizona, USA; Department of Otolaryngology, University of Arizona, USA; Arizona Cancer Center, University of Arizona, USA; BIO5 Institute, University of Arizona, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jacob
keywords: AKT; Autophagy; Integrin-linked kinase; OSU-T315; PDK2; Vestibular schwannoma