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PNAS 99 (22): 14098-14103

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer

Tohru Yamada*,{dagger}, Masatoshi Goto*,{dagger}, Vasu Punj*,{dagger}, Olga Zaborina*,{dagger},{ddagger}, Mei Ling Chen*, Kazuhide Kimbara*,§, Dibyen Majumdar, Elizabeth Cunningham||, Tapas K. Das Gupta||, and Ananda M. Chakrabarty*,**

Departments of *Microbiology and Immunology, Mathematics, Statistics, and Computer Sciences, and|| Surgical Oncology, University of Illinois, 835 South Wolcott Avenue, Chicago, IL 60612

Accepted for publication September 5, 2002.

Received for publication July 30, 2002.

Abstract: The use of live bacteria in the treatment of cancer has a long and interesting history. We report the use of a purified bacterial redox protein, azurin, that enters human cancer (melanoma UISO-Mel-2) cells and induces apoptosis. The induction of apoptosis occurs readily in melanoma cells harboring a functional tumor suppressor protein p53, but much less efficiently in p53-null mutant melanoma (UISO-Mel-6) cells. A redox-negative mutant form of azurin (M44K/M64E) demonstrates much less cytotoxicity to the UISO-Mel-2 cells than the wild-type protein. Azurin has been shown to be internalized in UISO-Mel-2 cells and is localized predominantly in the cytosol and in the nuclear fraction. In the p53-null UISO-Mel-6 cells, azurin is localized only in the cytosol. Thus, intracellular trafficking of azurin to the nucleus is p53-dependent. Azurin forms a complex with p53, thereby stabilizing it and raising its intracellular level in cytosolic, mitochondrial, and nuclear fractions. Corresponding to an increasing level of p53, an inducer of apoptosis, the level of Bax also increases in mitochondria, allowing significant release of mitochondrial cytochrome c into the cytosol, thus initiating the onset of apoptosis. The M44K/M64E mutant form of azurin, deficient in cytotoxicity, is also deficient in forming a complex with p53 and is less efficient in stabilizing p53 than wild-type azurin. Azurin has been shown to allow regression of human UISO-Mel-2 tumors xenotransplanted in nude mice and may potentially be used in cancer treatment.

{dagger} T.Y., M.G., O.Z., and V.P. contributed equally to this work.

{ddagger} Present address: Department of Surgery, University of Chicago Hospitals, Chicago, IL 60637.

§ Present address: Environment Biotechnology Laboratory, Railway Technical Research Institute, Tokyo 185-8540, Japan.

** To whom correspondence should be addressed. E-mail: pseudomo{at}uic.edu.

Communicated by Emanuel Margoliash, University of Illinois, Chicago, IL

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