Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells.
BACKGROUND
Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo.


RESULTS
In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition.


CONCLUSIONS
These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.
Tomohisa
T
Horibe
Aya
A
Torisawa
Masayuki
M
Kohno
Koji
K
Kawakami
D051943:Antennapedia Homeodomain Protein / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000633:toxicity; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry*; D010455:Peptides / Q000378:metabolism / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D056811:Unfolded Protein Response / Q000187:drug effects
D051943:Antennapedia Homeodomain Protein; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D028861:Nuclear Pore Complex Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; C073597:TPR protein, human; C112765:tanespimycin