title: An inhibitor of cholesterol absorption displays anti-myeloma activity by targeting the JAK2-STAT3 signaling pathway.
abstract: 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.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.affiliation: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Mao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Oncology, Suzhou Municipal Hospital East Campus, Suzhou, China.
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D004317:Doxorubicin; D002784:Cholesterol; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: JAK2; SC09; STAT3; multiple myeloma