Polo-like kinase 1 inhibition sensitizes neuroblastoma cells for vinca alkaloid-induced apoptosis.

Sebastian Czaplinski,Manuela Hugle,Simone Fulda,Valerie Stiehl

doi:10.18632/oncotarget.3901

Sebastian Czaplinski, Manuela Hugle + Show 2 more

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https://doi.org/10.18632/oncotarget.3901

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Abstract

High polo-like kinase 1 (PLK1) expression has been linked to poor outcome in neuroblastoma (NB), indicating that it represents a relevant therapeutic target in this malignancy. Here, we identify a synergistic induction of apoptosis by the PLK1 inhibitor BI 2536 and vinca alkaloids in NB cells. Synergistic drug interaction of BI 2536 together with vincristine (VCR), vinblastine (VBL) or vinorelbine (VNR) is confirmed by calculation of combination index (CI). Also, BI 2536 and VCR act in concert to reduce long-term clonogenic survival. Importantly, BI 2536 significantly enhances the antitumor activity of VCR in an in vivo model of NB. Mechanistically, BI 2536/VCR co-treatment triggers prolonged mitotic arrest, which is necessary for BI 2536/VCR-mediated apoptosis, since pharmacological inhibition of mitotic arrest by the CDK1 inhibitor RO-3306 significantly reduces cell death. Prolonged mitotic arrest leads to phosphorylation-mediated inactivation of BCL-2 and BCL-XL as well as downregulation of MCL-1, since inhibition of mitotic arrest by RO-3306 also prevents phosphorylation of BCL-2 and BCL-XL and MCL-1 downregulation. This inactivation of antiapoptotic BCL-2 proteins promotes activation of BAX and BAK, cleavage of caspase-9 and -3 and caspase-dependent apoptosis. Engagement of the mitochondrial pathway of apoptosis is critically required for BI 2536/VCR-induced apoptosis, since ectopic expression of a non-degradable MCL-1 phospho-mutant, BCL-2 overexpression or BAK knockdown significantly reduce BI 2536/VCR-mediated apoptosis. Thus, PLK1 inhibitors may open new perspectives for chemosensitization of NB.

Highlights

The prognosis of NB, a common solid tumor of childhood, remains poor especially for advanced and relapsed disease [1]
BI 2536/VCR co-treatment cooperated to significantly reduce colony formation compared to treatment with BI 2536 or VCR alone (Figure 1C). This set of experiments shows that the polo-like kinase 1 (PLK1) inhibitor BI 2536 synergistically cooperates with vinca alkaloids to induce apoptosis and to reduce long-term clonogenic growth of NB cells
Searching for rational combination treatments, we investigated the potential of the PLK1 inhibitor BI 2536 to sensitize NB cells for chemotherapy

Summary

Introduction

The prognosis of NB, a common solid tumor of childhood, remains poor especially for advanced and relapsed disease [1]. This highlights the demand for the development of novel therapeutic strategies. Apoptosis is a form of programmed cell death that is activated upon treatment with various anticancer drugs [2]. Signaling via the intrinsic (mitochondrial) pathway is critical for proper activation of caspases in the course of anticancer drug treatment and is tightly controlled by pro- and antiapoptotic proteins [3]. Antiapoptotic proteins of the BCL-2 family such as BCL-2, BCL-XL and MCL-1 as well as the proapoptotic members BAX and BAK play an important role in regulating mitochondrial outer membrane permeabilization [4]

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