Sci. Signal., 18 May 2010
Cancer Fueling the Cancer Cell
L. Bryan Ray
Science, Science Signaling, AAAS, Washington, DC 20005, USA
Attention has focused recently on the altered metabolism of tumor cells and the possibility that better understanding of metabolic differences between transformed and nontransformed cells might provide new means of battling cancer. Weinberg et al. analyzed the metabolic requirements of various cell lines transformed with the Kras oncogene. Increased aerobic glycolysis is characteristic of some cancer cells, so the authors tested whether glycolysis was required for proliferation of colon cancer cells with a Kras mutation in soft agar. If glycolysis was inhibited by depletion of glucose 6-phosphate isomerase with shRNA, but the pentose phosphate pathway remained active, cells were dependent on mitochondrial metabolism for survival, but the number of colonies formed in soft agar was unaffected. However, the colony size was limited, indicating that cells were unable to grow in hypoxic conditions. Thus the primary role of glucose metabolism in these cells seems to be production of intermediates for the pentose phosphate pathway, whereas glycolytic production of ATP allows growth in hypoxic conditions. Pharmacological inhibition of the TCA (tricarboxylic acid) cycle showed that catabolism of glutamine in the TCA cycle was required for colony formation. To test whether generation of reactive oxygen species (ROS) in mitochondria influenced proliferation of the cancer cells, the authors targeted nitroxides to the mitochondria to prevent ROS production. Such treatment decreased the number of colonies formed in soft agar and caused an increase in phosphorylation of mitogen-activated protein (MAP) kinases ERK1 and ERK2. Pharmacological inhibition of the MAP kinase signaling pathway restored colony formation in the nitroxide-treated cells, indicating that ROS may act by inhibiting activity of the MAP kinase pathway. By manipulating mitochondrial DNA, the authors showed that cells that did not produce ROS failed to grow in an anchorage-independent manner. Cells that could generate ROS but were deficient in oxidative phosphorylation did grow in soft agar. Further evidence that mitochondrial metabolism does contribute to tumor growth in vivo was obtained from mice in which alleles encoding a mitochondrial transcription factor were disrupted, resulting in defects in electron transport and oxidative phosphorylation. Retrovirally induced tumors containing Kras in such animals were smaller and less abundant than those in control animals. The authors conclude that glycolysis in cancer cells primarily feeds intermediates to the pentose phosphate pathway to support synthesis of nucleotides and phospholipids but is used in hypoxic conditions to generate ATP. A requirement for glutamine, previously noted for Myc-transformed cells, may be a more general requirement of cancer cells, and a supply of substrates to the TCA cycle is apparently also a requirement for tumorigenicity.
F. Weinberg, R. Hamanaka, W. W. Wheaton, S. Weinberg, J. Joseph, M. Lopez, B. Kalyanaraman, G. M. Mutlu, G. R. S. Budinger, N. S. Chandel, Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. U.S.A. 107, 8788–8793 (2010). [Abstract] [Full Text]
Citation: L. B. Ray, Fueling the Cancer Cell. Sci. Signal. 3, ec153 (2010).
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