Inhibition of melanoma tumor growth in vivo by survivin targeting.
A role of apoptosis (programmed cell death) in tumor formation and growth was investigated by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (Thr(34)-->Ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of survivin Thr(34)-->Ala in YUSAC2 melanoma cells prevented tumor formation upon s.c. injection into CB.17 severe combined immunodeficient-beige mice. When induced in established melanoma tumors, survivin Thr(34)-->Ala inhibited tumor growth by 60-70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy.
Grossman
D
D
Departments of Dermatology and Pathology and the Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Kim
P J
PJ
Schechner
J S
JS
Altieri
D C
DC
D019943:Amino Acid Substitution; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D018390:Gene Targeting; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008545:Melanoma / Q000473:pathology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013379:Substrate Specificity; D000077022:Survivin; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D016203:CDC2 Protein Kinase; D002945:Cisplatin