Linking Cancer and Metabolism
7 December 2012
Leslie K. Ferrarelli, Nancy R. Gough
Lewis Cantley (Weill Cornell Medical College) divided his talk into three parts: an introduction to the mTOR pathway, a discussion of the role of AMPK and Akt in regulation of metabolism, and a discussion of why type II diabetes may be associated with increased cancer risk. It seems that in metabolism and cell growth, all roads lead to mammalian target of rapamycin (mTOR). In particular, the mTOR complex 1 (mTORC1) functions as a critical logic gate so that cells only grow when there are sufficient nutrients (sensed through the Rag proteins to activate mTOR), growth factors [sensed by receptor tyrosine kinases (RTKs) that signal through phosphoinositide 3-kinase (PI3K) to activate mTOR], and ATP [sensed by AMP-regulated kinase (AMPK)]. Cantley noted that 80% of mutated genes currently identified in cancers encode signaling proteins involved in the RTK-PI3K-Akt-Ras-AMPK-mTOR pathway, and that PI3K-driven cancers are dependent on enhanced glucose metabolism. In this pathway, Akt and AMPK function in opposition to produce long-term effects on metabolism and growth that are mediated through changes in transcription. In contrast, for the acute regulation of metabolism, Akt and AMPK work in concert. He then described his lab’s work on a molecular mechanism through which AMPK inhibits degradation of glucose transporters during periods of acute energy stress. Although the mTOR network holds a key to cancer treatment, learning how to effectively target it is challenging, due to the multiple pathways through which mTOR can be activated and the rewiring that occurs in cancer cells.
Intriguingly, the high association of cancer with type II diabetes may be rooted in the misguided (albeit well-intentioned) treatment of patients with insulin to overcome insulin resistance. In many type II diabetes patients, circulating insulin and the related hormone IGF-1 are high because of the adaptive changes resulting from the loss of tissue responsiveness to insulin. Because insulin drives PI3K signaling, treatment of diabetes with insulin would provide a tremendous growth signal to the tumor cells. To limit this cancer-diabetes connection, better strategies for treating type II diabetes are to target metabolism, such as AMPK, a component of the mTOR pathway, or to target proteins that improve the tissue responsiveness to insulin, such as the transcriptional regulator PPARγ.
David Sabatini (Whitehead Institute, MIT) continued the theme of complexity in the mTOR network by showing that mTOR is not only regulated by most, if not all, external cues (such as nutrients, growth factors, mitogens, and hormones), but in turn regulates numerous key metabolic and growth pathways. He described his lab’s efforts to understand how the Rag family of guanosine triphosphatases (GTPases) enable mTORC1 activation by amino acids and described how mTORC1 makes the lysosome an intracellular metabolic-sensing organelle. The Rag proteins function as a complex, containing either Rag A or B with either Rag C or D, and the specific activated GTPase affects the function of the complex. For example, RagB-GDP/RagD-GTP does not bind to mTORC1, but RagB-GTP/RagD-GDP does. In the presence of amino acids, Rag proteins recruit mTORC1 to the surface of lysosomes, where the other GTPase that activates mTORC1 in response to both growth factors and sufficient energy supplies is found. Rag proteins themselves may shuttle on and off the lysosome, and the four possible states of this dimeric complex may be involved in its ability to recruit and transport mTORC1 to the lysosome. His lab is investigating how amino acids stimulate the lysosomally localized mTORC1 using isolated lysosome preparations. His lab is also trying to understand the connection between lysosomal function, mTORC1, and autophagy by examining RagA-GTP knock-in mice, which die postnatally and cannot initiate autohpagy, suggesting that autophagy is required to produce cell nutrients prior to suckling. Thus, not only is mTORC1 central to cancer metabolism, but is likely also critical for early postnatal survival through regulation of metabolism by influencing lysosomal activity and autophagy.
William Kaelin (Dana-Farber Cancer Institute) highlighted work in "oncometabolites," which are products of metabolism that can promote cancer. He described the conundrum that the transcription factor hypoxia-inducible factor 1α (HIF-1α), which enables cells to adapt to a low oxygen environment, is typically considered oncogenic, but in some cancers HIF-1α appears to function as a tumor suppressor. In particular, cancers with mutant forms of isocitrate dehydrogenase (IDH), which would produce large amounts of 2-hydroxyglutarate (2-HG), exhibit reduced abundance of HIF-1α. 2-HG affects the activity of enzymes in the 2-oxoglutarate-dependent dioxygenase family, which includes the histone demethylase JmjC and the prolyl hydroxylase PHD (also known as EGLN) family, the latter of which reduce the abundance of HIF-1α protein by marking it for proteasomal degradation. 2-HG is not the only “oncometabolite”; in cancers with mutations in various metabolic enzymes, such as succinate dehydrogenase (SDH), fumarate hydratase (FH), or isocitrate dehydrogenase (IDH), large amounts of endogenous metabolites accumulate (fumarate, succinate, and 2-HG, respectively) and these each influence carcinogenesis or cancer cell metabolism to confer a growth advantage.
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L. Bar-Peled, L. D. Schweitzer, R. Zoncu, D. M. Sabatini, Ragulator is a GEF for the RAG GTPases that signal amino acid levels to mTORC1. Cell 150, 1196-1208 (2012). [PubMed].
W. G. Kaelin, Jr. Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol. 76, 335-45 (2011). [PubMed].
P. Koivunen, S. Lee, C. G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J. A. Losman, P. Joensuu, U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K. L. Ligoon, R. G. Verhaak, H. Yan, W. G. Kaelin, Jr. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488 (2012). [PubMed].
Related Resources in Science Signaling
A. Roczniak-Ferguson, C. S. Petit, F. Froehlich, S. Qian, J. Ky, B. Angarola, T. C. Walther, S. M. Ferguson. The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Sci. Signal. 5, ra42. (2012). [Abstract] [Full Text].
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