한빛사 논문
Chaoyun Pan,1 Jaemoo Chun,1 Dan Li,1 Austin C. Boese,1 Jie Li,1 JiHoon Kang,1 Anna Umano,1 Yunhan Jiang,2 Lina Song,2 Kelly R. Magliocca,3 Zhuo G. Chen,1 Nabil F. Saba,1 Dong M. Shin,1 Taofeek K. Owonikoko,1 Sagar Lonial,1 Lingtao Jin,2,* and Sumin Kang1,*
1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia, USA. 2 Department of Anatomy and Cell Biology, University of Florida, College of Medicine, Gainesville, Florida, USA. 3Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
CP and JC contributed equally to this work.
*Address correspondence to: Sumin Kang, Emory University School of Medicine, Winship Cancer Institute, Suite C3006, 1365-C Clifton Road NE, Atlanta, Georgia 30322, USA. Or to: Lingtao Jin, University of Florida, College of Medicine, Cancer and Genetics Research Complex, Suite 456, 2033 Mowry Road, Gainesville, Florida 32608, USA.
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.
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