An inhibitor of cholesterol absorption displays anti-myeloma activity by targeting the JAK2-STAT3 signaling pathway
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Xin Xu1,*, Kunkun Han1,*, Jingyu Zhu2, Hongwu Mao1, Xu Lin1, Zubin Zhang1, Biyin Cao1, Yuanying Zeng3, Xinliang Mao1,4
1Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
2School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China
3Department of Oncology, Suzhou Municipal Hospital East Campus, Suzhou, China
4Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
*These authors have contributed equally to this work
Yuanying Zeng, email: [email protected]
Xinliang Mao, email: [email protected]
Keywords: JAK2, STAT3, multiple myeloma, SC09
Received: May 31, 2016 Accepted: September 16, 2016 Published: September 26, 2016
The activated JAK2-STAT3 signaling pathway is a high risk factor for multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, SC09, a potential inhibitor of cholesterol absorption, was identified in a STAT3-targeted drug screen. SC09 suppressed the activation of STAT3 in a time-course and concentration-dependent manner but did not affect its family members STAT1 and STAT5. SC09 inhibited STAT3 transcriptional activity and downregulated the expression of STAT3-regulated genes. Further studies showed that SC09 selectively inhibited JAK2 activation but not other kinases including c-Src, ERK, p38 and mTOR that are all associated with STAT3 activation. Moreover, SC09 obviously induced MM cell death in vitro and delayed MM tumor growth in vivo. SC09-induced MM cell death was dependent on the endogenous STAT3 status, and this effect could be attenuated by enforced expression of STAT3. All the results collectively indicated that SC09 blocks the JAK2-STAT3 signaling thus displaying anti-MM activity. Given its well tolerance and anti-MM potency, SC09 is credited for further investigation as a promising drug for MM treatment.
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