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J. Biol. Chem., Vol. 283, Issue 13, 8624-8633, March 28, 2008

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Anti-cancer Effects of JKA97 Are Associated with Its Induction of Cell Apoptosis via a Bax-dependent and p53-independent Pathway^*

Wenjing Luo¹, Jinyi Liu¹, Jingxia Li, Dongyun Zhang, Mingchao Liu, James K. Addo^¶, Shivaputra Patil^¶, Lin Zhang^||, Jian Yu^||, John K. Buolamwini^¶2, Jingyuan Chen³, and Chuanshu Huang⁴

From the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, Department of Occupational and Environmental Health Sciences, Fourth Military Medical University, 17 Changlexi Road, Xi'an, Shanxi 710032, China, ^¶Department of Pharmaceutical Sciences College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and ^||Departments of Pharmacology and Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

p53, one of the most commonly mutated genes in human cancers, is thought to be associated with cancer development. Hence, screening and identifying natural or synthetic compounds with anti-cancer activity via p53-independent pathway is one of the most challenging tasks for scientists in this field. Compound JKA97 (methoxy-1-styryl-9H-pyrid-[3,4-b]-indole) is a small molecule synthetic anti-cancer agent, with unknown mechanism(s). In this study we have demonstrated that the anti-cancer activity of JKA97 is associated with apoptotic induction via p53-independent mechanisms. We found that co-incubation of human colon cancer HCT116 cells with JKA97 inhibited HCT116 cell anchorage-independent growth in vitro and tumorigenicity in nude mice and also induced a cell apoptotic response, both in the cell culture model and in a tumorigenesis nude mouse model. Further studies showed that JKA97-induced apoptosis was dramatically impaired in Bax knock-out (Bax^-/-) HCT116 cells, whereas the knock-out of p53 or PUMA did not show any inhibitory effects. The p53-independent apoptotic induction by JKA97 was confirmed in other colon cancer and hepatocarcinoma cell lines. In addition, our results showed an induction of Bax translocation and cytochrome c release from the mitochondria to the cytosol in HCT116 cells, demonstrating that the compound induces apoptosis through a Bax-initiated mitochondria-dependent pathway. These studies provide a molecular basis for the therapeutic application of JKA97 against human cancers with p53 mutations.

Received for publication, September 19, 2007 , and in revised form, January 23, 2008.

^* This work was supported by National Institutes of Health (NIH)/NCI Grants CA094964 (to C. H.), CA112557 (to C. H.), CA103180 (to C. H.), and CA1002102 (to J. K. B.) and NIH/NIEHS Grants ES012451 and ES000260. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: jbuolamw{at}utmem.edu.

³ To whom correspondence may be addressed. E-mail: jy_chen{at}fmmu.edu.cn.

⁴ To whom correspondence may be addressed: Nelson Inst. of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987. Tel.: 845-731-3519; Fax: 845-351-2320; E-mail: chuanshu{at}env.med.nyu.edu.

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