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First published online January 24, 2007
doi: 10.1242/10.1242/jcs.03349

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Metabolic catastrophe as a means to cancer cell death

¹ Department of Pharmacology, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
² University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
³ Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
⁴ Department of Medicine, 195 Little Albany Street, New Brunswick, NJ 08903, USA
⁵ Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers University, 679 Hoes Lane, Piscataway, NJ 08854, USA

^* Author for correspondence (e-mail: ewhite{at}cabm.rutgers.edu)

Accepted 17 October 2006

During tumorigenesis, normal growth mechanisms are deregulated and safeguards that eliminate abnormal cells by apoptosis are disabled. Tumor cells must also increase nutrient uptake and angiogenesis to support the upregulation of metabolism necessary for unrestricted growth. In addition, they have to rely on inefficient energy production by glycolysis. This glycolytic state can result from mutations that promote cell proliferation, the hypoxic tumor microenvironment and perhaps mitochondrial malfunction. Moreover, the very signals that enable unrestricted cell proliferation inhibit autophagy, which normally sustains cells during nutrient limitation. In tumors, inactivation of the autophagy pathway may enhance necrosis and inflammation and promote genomic instability, which can further enhance tumor growth. Thus, tumor cells cannot adapt efficiently to metabolic stress and could be induced to die by metabolic catastrophe, in which high energy demand is contrasted by insufficient energy production. Efforts to exploit this unique metabolic state clinically previously focused mainly on detecting tissue displaying increased glycolytic metabolism. The challenge now is to induce metabolic catastrophe therapeutically as an approach to killing the unkillable cells.

Key words: Autophagy, Apoptosis, AKT, mTOR, BCL-2, Beclin1, Cancer

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