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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

View larger version (128K): [in this window] [in a new window]   Fig. 1. Distinct morphological features of apoptosis, necrosis and autophagy. Immortal baby mouse kidney epithelial (iBMK) cell lines competent for apoptosis (wild-type), necrosis (apoptosis-defective and autophagy disabled by AKT activation) and autophagy (apoptosis defective) (Degenhardt et al., 2002; Degenhardt et al., 2006; Degenhardt and White, 2006) were subjected to metabolic stress (ischemia) for up to five days. Morphological changes were observed by time-lapse microscopy (100x). Representative individual cells from each cell line were followed for the indicated times, beginning immediately prior to any signs of altered morphology in metabolic stress (13.5 hours for wild-type, 16.6 hours for apoptosis- and autophagy-defective and 52.6 hours for apoptosis-defective cells). Cells undergoing apoptosis or necrosis are not viable at the end of each specified time, whereas cells capable of autophagy by virtue of an apoptotic defect retained viability for more than five days (Degenhardt et al., 2006). Following 112 hours of metabolic stress, apoptosis-defective cells that underwent autophagy were returned to normal culture conditions and photographed to document recovery (Degenhardt et al., 2006). The majority of these cells were able to recover and proliferate upon restoration of nutrients, and a representative cell is shown. Reproduced in part from Degenhardt et al. (Degenhardt et al., 2006) with permission from Elsevier.

View larger version (22K): [in this window] [in a new window]   Fig. 2. Differential response of normal and tumor cells to metabolic stress. Normal cells regulate cell growth in response to nutrient availability by modulating the activity of the PI 3-kinase pathway, which through mTOR promotes cell growth and downregulates the catabolic process of autophagy. In periods of starvation, normal cells downregulate mTOR, which slows cell growth, while upregulating autophagy to allow adaptation to metabolic stress. In contrast, tumor cells frequently acquire mutations that constitutively activate the PI 3-kinase pathway that efficiently promotes cell growth in the presence of nutrients. In starvation conditions, however, tumor cells inefficiently adapt to metabolic stress through the failure to downregulate cell growth and upregulate autophagy, which can result in apoptotic or necrotic cell death though metabolic catastrophe.

View larger version (28K): [in this window] [in a new window]   Fig. 3. How manipulation of tumor cell metabolism can be used to induce cell death by metabolic catastrophe. The difference between normal and tumor cell metabolism can be exploited for cancer therapy by promoting metabolic catastrophe. mTOR inhibitors, such as rapamycin and its analogues in this case, are an effective means to limit tumor cell growth (Faivre et al., 2006). Alternatively, metabolic catastrophe can be achieved by therapeutic starvation, by restricting nutrient availability, uptake and utilization, by enhancing consumption or by preventing catabolism through autophagy.

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