This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-0349v1 69/21/8356    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Seo, Y.-W. Articles by Kim, T.-H. PubMed PubMed Citation Articles by Seo, Y.-W. Articles by Kim, T.-H.

The Cell Death–Inducing Activity of the Peptide Containing Noxa Mitochondrial-Targeting Domain Is Associated with Calcium Release

Departments of ¹ Biochemistry, ² Anatomy, and ³ Medical Science and Engineering Research Center for Resistant Cells, Chosun University School of Medicine; ⁴ Korea Basic Science Institute Gwang-Ju Center; and ⁵ Department of Pharmacology, Chonnam National University School of Medicine, Gwang-ju, Korea; ⁶ School of Life Science and Biotechnology, Korea University and ⁷ Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, Korea; ⁸ Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea; ⁹ Saban Research Institute, Childrens Hospital Los Angeles, Division of Pediatric Urology, University of Southern California Keck School of Medicine, Los Angeles, California; ¹⁰ Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; ¹¹ Gachon BioNano Research Institute and Department of Life Science, Kyungwon University, Sungnam, Korea; and ¹² Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: Dr. Tae-Hyoung Kim, Room # 2205, Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwang-ju, 501-759, Korea, Phone: +82-62-230-6294; Fax: +82-62-226-4165; E-mail: thkim65{at}mail.chosun.ac.kr.

DNA damage stabilizes the p53 tumor suppressor protein that determines the cell fate by either cell cycle arrest or cell death induction. Noxa, the BH3-only Bcl-2 family protein, was shown to be a key player in p53-induced cell death through the mitochondrial dysfunction; however, the molecular mechanism by which Noxa induces the mitochondrial dysfunction to cause cell death in response to genotoxic agents is largely unknown. Here, we show that the mitochondrial-targeting domain (MTD) of Noxa is a prodeath domain. Peptide containing MTD causes massive necrosis in vitro through cytosolic calcium increase; it is released from the mitochondria by opening the mitochondrial permeability transition pore. MTD peptide–induced cell death can be inhibited by calcium chelator BAPTA-AM. Moreover, MTD peptide shows the potent tumor-killing activities in mice by joining with tumor-homing motifs. [Cancer Res 2009;69(21):8356–65]

Key Words: Noxa • Bcl-2 family • mitochondrial targeting domain • calcium release • apoptosis • necrosis