Tumor growth suppression using a combination of taxol-based therapy and GSK3 inhibition in non-small cell lung cancer.

Linda O’Flaherty,Olivier E Pardo,Stephen J Cross,Steven D Shnyder,James G Wakefield,Michael J Seckl,Jeremy M Tavaré,Patricia A Cooper,Sumitra Deb

doi:10.1371/journal.pone.0214610

Abstract

Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer.

Highlights

It is well established that glycogen synthase kinase-3 (GSK3) phosphorylates a wide range of protein substrates which, in turn, regulate a plethora of cellular processes including the control of cell metabolism, differentiation, proliferation and apoptosis [1,2,3,4,5]
In this study we examined three non-small cell lung carcinoma (NSCLC) cell lines (H1975, H1299 and HCC193) for the effects of CHIR99021 on cell growth when used alone or in combination with the chemotherapeutic agent, paclitaxel
To explore the mechanism by which GSK3 contributes to cell proliferation, we examined the effects of CHIR99021 and paclitaxel on chromosomal alignment in metaphase cells

Summary

Introduction

It is well established that glycogen synthase kinase-3 (GSK3) phosphorylates a wide range of protein substrates which, in turn, regulate a plethora of cellular processes including the control of cell metabolism, differentiation, proliferation and apoptosis [1,2,3,4,5]. Considering this multifunctionality, it is not surprising that GSK3 has been implicated in several diseases ranging from schizophrenia, neurodegeneration and diabetes, to cancer [6,7,8]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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