Enhancement of Bik antitumor effect by Bik mutants.
Bik was initially identified as a BH3-domain-only protein that interacts with E1B 19K. Although systemically administered wild-type Bik significantly inhibited tumor growth and metastasis in an orthotopic nude mouse model, the proapoptotic potency of Bik can be modulated by posttranslational phosphorylation. Here, we found that Bik mutants, in which threonine 33 and/or serine 35 were changed to aspartic acid to mimic the phosphorylation at these two residues, enhanced their binding affinity with the antiapoptotic proteins Bcl-X(L) and Bcl-2 and were more potent than wild-type Bik in inducing apoptosis and inhibiting cell proliferation in various human cancer cells. Bik mutants also suppressed tumorigenicity and tumor-taking rate in a mouse ex vivo model. Moreover, Bik mutant-liposome complexes inhibited tumor growth and prolonged life span more effectively than the wild-type Bik-liposome complex in an in vivo orthotopic animal model. Thus, our results demonstrate that Bik mutant genes, more potent than wild-type Bik, induce cell death and suggest that their inhibition on the growth of various cancers should be explored further.
Li
Yan M
YM
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Wen
Yong
Y
Zhou
Binhua P
BP
Kuo
Hsu-Ping
HP
Ding
Qingqing
Q
Hung
Mien-Chie
MC
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C096820:BIK protein, human; C494812:Bcl2l1 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein