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[Cancer Research 60, 6818-6821, December 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Selective Toxicity of MKT-077 to Cancer Cells Is Mediated by Its Binding to the hsp70 Family Protein mot-2 and Reactivation of p53 Function

Renu Wadhwa1, Takashi Sugihara, Akiko Yoshida, Hitoshi Nomura, Roger R. Reddel, Richard Simpson, Hiroshi Maruta and Sunil C. Kaul

Chugai Research Institute for Molecular Medicine, 153-2 Nagai, Niihari, Ibaraki 300-41, Japan [R. W., T. S., A. Y., H. N.]; Children’s Medical Research Institute, Sydney, New South Wales 2145, Australia [R. R. R.]; Ludwig Institute for Cancer Research, Melbourne, Victoria 3050, Australia [R. S., H. M.]; National Institute of Bioscience and Human-Technology, 1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan [S. C. K.]

MKT-077, a cationic rhodacyanine dye analogue has been under preclinical cancer therapeutical trials because of its selective toxicity to cancer cells. Its cellular targets and mechanism of action remain poorly understood. Here we report that MKT-077 binds to an hsp70 family member, mortalin (mot-2), and abrogates its interactions with the tumor suppressor protein, p53. In cancer cells, but not in normal cells, MKT-077 induced release of wild-type p53 from cytoplasmically sequestered p53-mot-2 complexes and rescued its transcriptional activation function. Thus, MKT-077 may be particularly useful for therapy of cancers with wild-type p53.




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