title: Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells.
abstract: 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.
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Zhejiang, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Sa
authors.initials: S
authors.lastname: Deng
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Baojing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002018:Bufanolides; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C000612263:gamabufotalin; C465283:WWP2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: WWP2; c-Myc; degradation; gamabufotalin; multiple myeloma