Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation
Chaoyun Pan, … , Lingtao Jin, Sumin Kang
Chaoyun Pan, … , Lingtao Jin, Sumin Kang
Published October 1, 2019; First published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4110-4123. https://doi.org/10.1172/JCI125963.
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Research Article Oncology Therapeutics

Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation

Abstract

Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers.

Authors

Chaoyun Pan, Jaemoo Chun, Dan Li, Austin C. Boese, Jie Li, JiHoon Kang, Anna Umano, Yunhan Jiang, Lina Song, Kelly R. Magliocca, Zhuo G. Chen, Nabil F. Saba, Dong M. Shin, Taofeek K. Owonikoko, Sagar Lonial, Lingtao Jin, Sumin Kang

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Figure 1

Hsp90B binds to and stabilizes MAST1 in cisplatin-resistant cancer cells.

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Hsp90B binds to and stabilizes MAST1 in cisplatin-resistant cancer cells...
(A) 2D gel electrophoresis–based proteomic analysis for MAST1-interacting protein identification. 293T cells expressing GST-MAST1 or GST alone were subjected to GST pull down and eluates were separated by 2D gel electrophoresis and visualized by silver staining. Black arrow indicates hsp90B only shown in GST-MAST1 eluates. (B) MS spectra of hsp90B fragment identified by LC-MS/MS. (C) Endogenous interaction between MAST1 and hsp90B was determined by MAST1 coimmunoprecipitation in cisplatin-resistant cancer cells. (D and E) Interaction of hsp90 isoforms with MAST1. Interaction was determined by coimmunoprecipitation. Myc-MAST1 and flag-hsp90B or hsp90A1 were overexpressed in KB-3-1cisR and A549cisR cells in E. (F) Effect of hsp90 inhibition on MAST1 protein level. Cisplatin-resistant cancer cells were treated with increasing concentrations of 17-AAG for 24 hours. MAST1 protein levels were determined by Western blotting. Data are representative of 2 (A and C–E) and 3 (F) independent biological experiments.