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Research Articles: Therapeutics, Targets, and Development

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNF-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

¹ Department of Pharmacology, College of Medicine, National Taiwan University and ² Cancer Center, Veterans General Hospital, Taipei, Taiwan

Requests for reprints: Wan-Wan Lin, Department of Pharmacology, College of Medicine, National Taiwan University, Room 1119, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan. Phone: 886-2-23123456, ext. 8315; Fax: 886-2-23915297. E-mail: wwl{at}ha.mc.ntu.edu.tw

Abstract

Death receptor-mediated tumor cell death, either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. In this study, we have investigated the effects and molecular mechanisms of 5-aminoimidazole-4-carboxamide riboside [AICAR; a pharmacologic activator of AMP-activated protein kinase (AMPK)] in sensitizing tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL)– and TNF-induced apoptosis of human colon cancer HCT116 cells. The cytotoxic action of AICAR requires AMPK activation and may occur at various stages of apoptotic pathways. AICAR cotreatment with either TRAIL or TNF enhances activities of caspase-8, caspase-9, and caspase-3; down-regulates the antiapoptotic protein Bcl-2; increases the cleavage of Bid and results in the decrease of mitochondrial membrane potential; potentiates activation of p38 and c-Jun NH₂-terminal kinase; and inhibits nuclear factor-B activity. In addition, this sensitized cell apoptosis was neither observed in p53-null HCT116 cells nor affected by the cotreatment with mevalonate. In summary, we have developed a novel strategy of combining AICAR with TRAIL for the treatment of colon cancer cells. The sensitization effect of AICAR in cell apoptosis was mediated through AMPK pathway, requires p53 activity, and involves mitochondria-dependent apoptotic cascades, p38 and c-Jun NH₂-terminal kinase. [Mol Cancer Ther 2007;6(5):1562–71]

Grant support: National Science Council, Taiwan grants NSC 95-2314-B-075-089-MY2 and NSC 95-2320-B-002-092-MY3.

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.

Received 12/27/06; revised 3/ 2/07; accepted 3/27/07.

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