Oncotarget

Research Papers:

Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells

Chia-Lung Tsai, Angel Chao, Shih-Ming Jung, Chi-Neu Tsai, Chiao-Yun Lin, Shun-Hua Chen, Shih-Che Sue, Tzu-Hao Wang _, Hsin-Shih Wang and Chyong- Huey Lai

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Oncotarget. 2016; 7:50548-50563. https://doi.org/10.18632/oncotarget.10500

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Abstract

Chia-Lung Tsai1,*, Angel Chao1,2,*, Shih-Ming Jung3, Chi-Neu Tsai4, Chiao-Yun Lin2, Shun-Hua Chen2,5, Shih-Che Sue6, Tzu-Hao Wang1,2,7, Hsin-Shih Wang2, Chyong-Huey Lai2

1Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan

2Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

3Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

4Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

5Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan

6Department of Life Sciences, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan

7School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Tzu-Hao Wang, email: knoxtn@cgmh.org.tw

Keywords: JAK2, STIP1, cancer

Received: March 08, 2016     Accepted: June 17, 2016     Published: July 8, 2016

ABSTRACT

Overexpression of stress-induced phosphoprotein 1 (STIP1) − a co-chaperone of heat shock protein (HSP) 70/HSP90 – and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.


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