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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.
PMID
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Authors

Mayor MeshTerms
Keywords

AKT

Autophagy

Integrin-linked kinase

OSU-T315

PDK2

Vestibular schwannoma

Journal Title austin journal of medical oncology
Publication Year Start




PMID- 27642646
OWN - NLM
STAT- Publisher
DA  - 20160919
LR  - 20160922
IS  - 2471-027X (Linking)
VI  - 3
IP  - 1
DP  - 2016
TI  - The Novel Small Molecule Inhibitor, OSU-T315, Suppresses Vestibular Schwannoma
      and Meningioma Growth by Inhibiting PDK2 Function in the AKT Pathway Activation.
LID - 1025 [pii]
AB  - 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 &lt; 2muM in VS (HEI193) and meningioma (Ben-Men-1) cell
      lines, in primary cells at &lt; 3.5muM, while in normal primary Schwann cells at
      7.1muM. 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.
FAU - Mercado-Pimentel, M E
AU  - Mercado-Pimentel ME
AD  - Ear Institute, University of Arizona, USA; Department of Otolaryngology,
      University of Arizona, USA; Arizona Cancer Center, University of Arizona, USA.
FAU - Igarashi, S
AU  - Igarashi S
AD  - Ear Institute, University of Arizona, USA; Department of Otolaryngology,
      University of Arizona, USA.
FAU - Dunn, A M
AU  - Dunn AM
AD  - Ear Institute, University of Arizona, USA; Department of Otolaryngology,
      University of Arizona, USA.
FAU - Behbahani, M
AU  - Behbahani M
AD  - Ear Institute, University of Arizona, USA; Department of Otolaryngology,
      University of Arizona, USA.
FAU - Miller, C
AU  - Miller C
AD  - Ear Institute, University of Arizona, USA; Department of Otolaryngology,
      University of Arizona, USA.
FAU - Read, C M
AU  - Read CM
AD  - Ear Institute, University of Arizona, USA.
FAU - Jacob, A
AU  - Jacob A
AD  - 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.
LA  - ENG
GR  - K08 DC009644/DC/NIDCD NIH HHS/United States
PT  - JOURNAL ARTICLE
DEP - 20160421
PL  - United States
TA  - Austin J Med Oncol
JT  - Austin journal of medical oncology
JID - 101685299
PMC - PMC5024787
MID - NIHMS794819
OTO - NOTNLM
OT  - AKT
OT  - Autophagy
OT  - Integrin-linked kinase
OT  - OSU-T315
OT  - PDK2
OT  - Vestibular schwannoma
EDAT- 2016/09/20 06:00
MHDA- 2016/09/20 06:00
CRDT- 2016/09/20 06:00
PST - ppublish
SO  - Austin J Med Oncol. 2016;3(1). pii: 1025. Epub 2016 Apr 21.

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