Cryptotanshinone inhibits proliferation yet induces apoptosis by suppressing STAT3 signals in renal cell carcinoma

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// Zhiguo Chen 1 , Rujian Zhu 2, 3 , Jiayi Zheng 4 , Chen Chen 2 , Chi Huang 2 , Junjie Ma 2 , Chen Xu 1 , Wei Zhai 1, 5 and Junhua Zheng 1 1 Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China 2 Department of Urology, The Affiliated Shanghai Tenth People’s Hospital, Nanjing Medical University, Shanghai, China 3 Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China 4 Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China 5 Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence to: Wei Zhai, email: jacky_zw2002@hotmail.com Junhua Zheng, email: zhengjh0471@sina.com.cn Keywords: cryptotanshinone, renal cell carcinoma, cell proliferation, cell apoptosis, STAT3 Abbreviations: CPT: cryptotanshinone; RCC: renal cell carcinoma; STAT3: signal transducer and activator of transcription 3; DMSO: dimethyl sulfoxide Received: January 23, 2017 Accepted: May 04, 2017 Published: June 15, 2017 ABSTRACT It has been established that signal transducer and activator of transcription 3 serves as an oncoprotein in various human cancers; targeting it is therefore a reasonable approach for emerging cancer therapies. Cryptotanshinone, a natural compound extracted from the root of Salvia miltiorrhiza Bunge, has been identified as a potential STAT3 inhibitor. However, its functional role in renal cell carcinomas remains largely unknown. Therefore, we investigated the mode of action for cryptotanshinone. We found that cryptotanshinone substantially suppressed cancer cell growth while it promoted cell apoptosis by inhibiting the phosphorylation of STAT3 at Tyr705 and its blocking nuclear translocation. Coordinately, P-AKT, CyclinD1, C-MYC, MEKK2, and HGF were down-regulated and cell cycle progression was arrested at the G0/G1 phase, thereby attenuating cell proliferation. Moreover, the level of Cleaved-Caspase-3 was elevated while Bcl-2 and Survivin were down-regulated, accounting for the increased apoptosis. Furthermore, in vivo results revealed that cryptotanshinone effectively inhibits tumorigenesis in an A498-xenografted mouse model. Taken together, our data gives a more comprehensive understanding of how cryptotanshinone functions in renal cell carcinomas and demonstrates its potential as a powerful therapeutic approach to treat renal cell carcinomas.