Oncotarget

Research Papers:

Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations

Michiya Sugimori _, Yumiko Hayakawa, Masaki Koh, Tomohide Hayashi, Ryoi Tamura and Satoshi Kuroda

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Oncotarget. 2018; 9:3043-3059. https://doi.org/10.18632/oncotarget.23077

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Abstract

Michiya Sugimori1,*, Yumiko Hayakawa2,*, Masaki Koh2, Tomohide Hayashi2, Ryoi Tamura1 and Satoshi Kuroda2

1Department of Integrative Neuroscience, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan

2Department of Neurosurgery, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan

*These authors contributed equally to this work

Correspondence to:

Michiya Sugimori, email: [email protected]

Satoshi Kuroda, email: [email protected]

Keywords: glioma stem cell (GSC); glioma sphere (GS); T-Lak cell originated protein kinase (TOPK); OTS964; power-law

Received: August 24, 2017     Accepted: November 14, 2017     Published: December 09, 2017

ABSTRACT

Glioblastoma resists chemoradiotherapy, then, recurs to be a fatal space-occupying lesion. The recurrence is caused by re-growing cell populations such as glioma stem cells (GSCs), suggesting that GSC populations should be targeted. This study addressed whether a novel anti-cancer drug, OTS964, an inhibitor for T-LAK cell originated protein kinase (TOPK), is effective in reducing the size of the heterogeneous GSC populations, a power-law coded heterogeneous GSC populations consisting of glioma sphere (GS) clones, by detailing quantitative growth properties. We found that OTS964 killed GS clones while suppressing the growth of surviving GS clones, thus identifying clone-eliminating and growth-disturbing efficacies of OTS964. The efficacies led to a significant size reduction in GS populations in a dose-dependent manner. The surviving GS clones reconstructed GS populations in the following generations; the recovery of GS populations fits a recurrence after the chemotherapy. The recovering GS clones resisted the clone-eliminating effect of OTS964 in sequential exposure during the growth recovery. However, surprisingly, the resistant properties of the recovered-GS clones had been plastically canceled during self-renewal, and then the GS clones had become re-sensitive to OTS964. Thus, OTS964 targets GSCs to eliminate them or suppress their growth, resulting in shrinkage of the power-law coded GSC populations. We propose a therapy focusing on long-term control in recurrence of glioblastoma via reducing the size of the GSC populations by OTS964.


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