Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells
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Zhenlong Yu1,*, Tao Li2,*, Chao Wang1, Sa Deng1, Baojing Zhang1, Xiaokui Huo1, Bo Zhang3, Xiaobo Wang1, Yuping Zhong4, Xiaochi Ma1
1College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China
2Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Zhejiang, China
3Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
4Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
*These authors contributed equally to this work
Bo Zhang, e-mail: Zhangbodl@126.com
Xiaochi Ma, e-mail: firstname.lastname@example.org
Keywords: gamabufotalin, multiple myeloma, c-Myc, degradation, WWP2
Received: October 13, 2015 Accepted: February 05, 2016 Published: February 15, 2016
Deciding appropriate therapy for multiple myeloma (MM) is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin (GBT) was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells. We found GBT inhibited cell growth and induced apoptosis with the IC50 values <50 nM. Mechanistic studies using functional approaches identified GBT as an inhibitor of c-Myc. Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. GBT treatment inhibited ERK and AKT signals, while stimulating the activation of JNK cascade. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. The antitumor effect of GBT was validated in a xenograft mouse model and the suppression of MM-induced osteolysis was verified in a SCID-hu model in vivo. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM.
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