Identification of Cdk1-LATS-Pin1 as a Novel Signaling Axis in Anti-tubulin Drug Response of Cancer Cells.

Benjamin Yeung,Xiaolong Yang,Prem Khanal,Virja Mehta,Laura Trinkle-Mulcahy

doi:10.1158/1541-7786.mcr-17-0684

Benjamin Yeung, Xiaolong Yang + Show 3 more

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https://doi.org/10.1158/1541-7786.mcr-17-0684

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Abstract

The Hippo pathway is a signaling cascade that plays important roles in organ size control, tumorigenesis, metastasis, stress response, stem cell differentiation, and renewal during development and tissue homeostasis and mechanotransduction. Recently, it has been observed that loss of the Hippo pathway core component LATS (large tumor suppressor) or overexpression of its downstream targets YAP and its paralog TAZ causes resistance of cancer cells to anti-tubulin drugs. However, YAP and TAZ mediates anti-tubulin drug-induced apoptosis independent of its upstream regulator LATS and the Hippo pathway. Thus, the underlying molecular mechanism of how LATS is involved in the anti-tubulin drug response remains unknown. Proteomic approaches, SILAC and BioID, were used to identify the isomerase Pin1 as a novel LATS-interacting protein after anti-tubulin drug treatment. Treatment with anti-tubulin drugs activated cyclin-dependent kinase 1 (CDK1), which phosphorylates LATS2 at five S/T-P motifs that functionally interact with the WW domain of Pin1 and inhibit its antiapoptotic function. Thus, these data identify Cdk1 and Pin1 as a novel upstream regulator and downstream mediator, respectively, of LATS in antitubulin drug response. Further studies on this novel Cdk1-LATS-Pin1 signaling axis will be important for understanding the molecular mechanisms of drug resistance and will provide useful information for targeting of this pathway in the future.Implications: This study provides new insight on the molecular mechanism of anti-tubulin drug resistance and suggests novel therapeutic targets for drug-resistant cancers. Mol Cancer Res; 16(6); 1035-45. ©2018 AACR.

Highlights

Anti-tubulin drugs, which include taxanes and vinca alkaloids, have been a part of the cancer pharmacopoeia for decades and are one of the most successful classes of chemotherapeutics to date [1, 2]
LATS2 is phosphorylated after anti-tubulin drug treatment To further explore how LATS1/2 is involved in drug response, we treated HeLa cells with DMSO or various antitubulin drugs for 24 hours and collected attached (DMSO) or floating cells
We noted that there was no change in endogenous levels of YAP or its phosphorylation at S127, further supporting the notion that LATS1/2 is involved in drug response through YAP-independent means (Fig. 1A)

Summary

Introduction

Anti-tubulin drugs, which include taxanes and vinca alkaloids, have been a part of the cancer pharmacopoeia for decades and are one of the most successful classes of chemotherapeutics to date [1, 2]. By inhibiting the polymerization dynamics of microtubules, anti-tubulin drugs are potent mitotic poisons that impede normal function of the mitotic spindle, leading to extended mitotic arrest and cell death [3]. Anti-tubulin drugs have proven to be clinically efficacious, predicting patient response is often difficult and the development of drug-resistant tumor cells leading to relapse/patient mortality continues to be a major challenge to successful treatment [1]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

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