Proteomic identification of the oncoprotein STAT3 as a target of a novel Skp1 inhibitor
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Xin Cheng1,*, Yong-Qiang Liu1,*, Gui-Zhen Wang1,*, Li-Na Yang2,*, Yong-Zhi Lu3, Xin-Chun Li1, Bo Zhou1, Li-Wei Qu1, Xiao-Lu Wang1, Yong-Xian Cheng4, Jinsong Liu3, Sheng-Ce Tao2, Guang-Biao Zhou1
1Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
2Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China
3Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
4State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
*These authors have contributed equally to this work
Guang-Biao Zhou, email: firstname.lastname@example.org
Sheng-Ce Tao, email: email@example.com
Keywords: proteome microarray, 6-O-angeloylplenolin, STAT3 inhibitor, Skp2, lung cancer
Received: July 25, 2016 Accepted: October 14, 2016 Published: November 7, 2016
The S phase kinase-associated protein 1 (Skp1), an adaptor protein of the Skp1-Cul1-F-box protein complex, binds the ubiquitin E3 ligase Skp2 and is critical to its biological functions. Targeting of Skp1 by a small compound 6-O-angeloylplenolin (6-OAP) results in dissociation and degradation of Skp2 and mitotic arrest of lung cancer cells. Here, by using a proteome microarray containing 16,368 proteins and a biotinylated 6-OAP, we identified 99 proteins that could bind 6-OAP, with Skp1 and STAT3 sitting at the central position of the 6-OAP interactome. 6-OAP formed hydrogen bonds with Ser611/Ser613/Arg609 at the SH2 domain of STAT3 and inhibited the constitutive and interleukin-6-induced phosphorylated STAT3 (pSTAT3), leading to inhibitory effects on lung cancer cells and suppression of Skp2 transcription. STAT3 was overexpressed in tumor samples compared to counterpart normal lung tissues and was inversely associated with prognosis of the patients. 6-OAP inhibited tumor growth in SCID mice intravenously injected with lung cancer cells, and downregulated both STAT3 and Skp2 in tumor samples. Given that 6-OAP is a Skp1 inhibitor, our data suggest that this compound may target Skp1 and STAT3 to suppress Skp2, augmenting its anti-lung cancer activity.
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