Metabolism and Cancer in La Jolla
Year: 2010
Type: article
Abstract: Studies from a number of laboratories in the past decade have revealed that the central pathways deregulated in cancer often serve to coordinately regulate both classic oncogenic signaling pathways controlling cell proliferation and cell survival with pathways controlling cell metabolism. The emergence of these findings, suggesting a direct control of cellular metabolism by tumorigenic pathways, has helped fuel explosive growth in this area of cancer research. Paralleling the emergence of targeted therapeutics in cancer treatment, a variety of experimental approaches has led to the conclusion that tumors bearing some specific genetic alterations may lead them to be uniquely sensitive to agents deregulating their cellular metabolism. Given this resurgence of research at these crossroads, Metabolism & Cancer was a special conference in Cancer Research held by the AACR from September 13 to 16, 2009 in La Jolla, California.Dr. Otto Warburg first described, more than 80 years ago, that a fundamental biochemical difference between tumor cells and their normal counterparts was that tumor cells rely on aerobic glycolysis for ATP generation, unlike most normal differentiated cells of the body, which use mitochondrial oxidative phosphorylation. As glycolysis is an inefficient method to produce ATP compared with oxidative phosphorylation, it remained a quandary why tumor cells might favor that mechanism. Keynote speakers Dr. Craig Thompson (University of Pennsylvania, Philadelphia, PA) and Dr. Lewis Cantley (Harvard Medical School, Boston, MA) set the stage for the meeting by providing an overview of our current understanding of the links between mammalian growth control and metabolic control. Unlike unicellular organisms, which simply upregulate operons of genes containing surface transporters and pathway components in response to the sensing of extracellular metabolites, in most cells multicellular organisms are in a constant supply of nutrients from the bloodstream. The discovery that mutations in tumor suppressors and oncogenes that promote cell survival and proliferation also stimulate nutrient uptake and alter cellular metabolism reinforces the concept that these processes are biochemically and molecularly integrated. Dr. Cantley also emphasized that, unlike glycolysis and the pentose shunt, oxidative phosphorylation cannot produce any NADPH or acetyl-coA, both of which are needed in abundance to produce phospholipids in proliferating cells. Thus the requirements for metabolic intermediates uniquely produced during glycolysis may underlie the favorable advantage it bestows on cancer cells. The PI3-kinase/mammalian target of rapamycin (mTOR) pathway and the myc pathway are centrally involved in the reprogramming of glucose and glutamine metabolism to fuel cell growth. Therefore, tumor cells bearing genetic alterations in components of these pathways become addicted to glucose and may show enhanced sensitivity to agents disrupting their energy metabolism. Whether metabolic disturbances can also explain higher rates of mutation in tumor cells remains an interesting area to investigate. Moreover, whether agents targeting key metabolic regulators—such as ATP citrate lyase, the DNA repair enzyme PARP, which requires NAD+, or the M2 splice isoform of pyruvate kinase, which the Cantley laboratory showed is critical for the proliferation of tumor cells—will be beneficial in the clinical setting remains an interesting area of ongoing investigation.Cells possess the capacity to sense and integrate diverse environmental signals, such as the availability of nutrients, oxygen, growth factors, and cytokines, and activity of cell adhesion molecules. However, the mechanisms underlying how eukaryotic cells integrate multiple signals to alter metabolism when faced with unfavorable conditions are less well understood. Several speakers discussed advances in our understanding of pathways that promote growth and are deregulated in many common cancers. The multiprotein mTORC1 protein kinase complex is a central component of pathways that promote growth in response to abundant levels of insulin, glucose, and amino acids. Dr. David Sabatini (Massachusetts Institute of Technology, Cambridge, MA) described how Rag proteins, a family of four related guanosine triphosphatases (GTPase), interact with mTORC1 in response to increased amino acid supplies and are necessary for mTORC1 activation by amino acids. These Rag proteins do not directly stimulate mTORC1 kinase activity, but promote the intracellular localization of mTORC1 to a Rab7+ compartment that also contains its activator Rheb. This finding explains why other activators of Rheb, like insulin and glucose, do not stimulate mTORC1 when cells are starved for amino acids. It seems likely that Rag function could be deregulated in a variety of human tumors, which will be an important question to investigate in the future. Consistent with these findings, Rory Flinn, from Dr. Jonathan Backer's laboratory (Albert Einstein College of Medicine, Bronx, NY), presented a short talk showing that blocking the early-to-late endosome conversion step using activated Rab5 alleles or loss of the Rab7 GEF hVps39 prevents mTOR from interacting with Rheb.TSC1 and TSC2 are tumor suppressor genes mutated in the tumor syndrome Tuberous Sclerosis Complex. Their gene products form a heterodimer that is a critical negative regulator of mTORC1, through the GTPase-activating protein activity of TSC2 toward Rheb. Because mTORC1 activity controls a variety of anabolic processes to promote cell growth, it is highly sensitive to alterations in the extracellular environment. As such, the TSC1/TSC2 complex senses many diverse extracellular signals to properly modulate mTORC1 activity. Dr. Brendan Manning (Harvard Medical School) described recent work with TSC-deficient mouse embryo fibroblasts discerning the transcriptional output of mTORC1 activity. He has determined that the expression of hundreds of genes change in the face of TSC1-deficiency and in an mTORC1-dependent manner (i.e., they are rapamycin sensitive). Most of the factors that change in TSC-deficient cells are those that participate in critical metabolic pathways, such as glycolysis, the pentose phosphate pathway, lipid-sterol biosynthesis, and the integrated stress response.Dr. Celeste Simon (University of Pennsylvania) focused on recent work involving a novel tumor suppressor gene known as Birt-Hogg-Dube (BHD). In multiple species, the pathologies of BHD are reminiscent of Tuberous Sclerosis Complex. Working with BHD-deficient mice and cells, the Simon laboratory has shown that BHD functions as a tumor suppressor by promoting the expression of the proapoptotic factor Bim downstream of TGFβ signaling. Of note, BHD-deficient tumors exhibit decreased Bim protein accumulation relative to adjacent control tissues.The key best-studied targets of mTORC1 kinase activity are the kinase S6K1 and the translational inhibitor 4EBP1, which blocks eIF4E. A short talk by Anne Marie Kenney (Memorial Sloan-Kettering Cancer Center) described how Sonic Hedgehog (SHH) signaling in cerebellular granule neuron precursors promotes cell growth and proliferation in a manner dependent on mTORC1. Surprisingly, there was no increase in S6K1 signaling in these cells, unlike effects on eIF4E stimulation. Further examination revealed evidence of crosstalk and feedback between these two mTORC1 effector pathways, which may be regulated at least in part via SHH-mediated increases in a subunit of the PP2A protein phosphatase.Dr. Almut Schulze (London Research Institute) described downstream targets of PI3K and mTOR signaling in the control of lipid synthesis. The sterol regulatory element binding protein (SREBP) family consists of three closely related members: SREBP1a, SREBP1c, and SREBP2. They mediate the effect of sterol on the expression of enzymes involved in lipid and cholesterol homeostasis. SREBP1 preferentially regulates genes involved in fatty acid biosynthesis. In contrast, SREBP2 regulates genes within the cholesterol pathway. It has been established that AKT induces the expression of a number of lipogenic genes, such as ATP citrate lyase and fatty acid synthase. Dr. Schulze has convincingly shown that SREBP- and AKT-dependent induction of lipid biosynthesis requires mTORC1 activity. Given that mTORC1 also promotes mRNA translation, the PI3K/AKT/mTORC1 pathway regulates protein and lipid biosynthesis in an orchestrated fashion. Moreover, both processes are required for cell growth. Because of the critical dependence of mutated cancer cells on these anabolic pathways, they may be “less metabolically flexible” and susceptible to targeted therapies that disrupt these processes.Evelien Rysman from the Swinnen Laboratory (KU Leuven, Belgium) gave a short talk on the crosstalk between SREBP1 and de novo lipogenesis within primary cilia, cellular structures that play key roles in development through modulation of Wnt and Hedgehog signaling pathways.Another central regulator of cellular metabolism is the AMP-activated protein kinase (AMPK). AMPK is activated under conditions of metabolic stress resulting in low intracellular ATP, such as when nutrients are low or following a number of pathological stresses. The kinase responsible for phosphorylating AMPK following metabolic stress is encoded by the LKB1 tumor suppressor, providing a direct connection between cell metabolism and tumorigenesis. However, in addition to AMPK, LKB1 also directly phosphorylates the activation loop threonine of 12 additional kinases all related to AMPK, drawing into question whether AMPK is the key target of LKB1 in its tumor suppressor function. Moreover, AMPK can also be phosphorylated by CAMKK2, in a manner dependent on increases in intracellular calcium. On the basis of the fact that CAMKK2 can serve as an alternative kinase for AMPK, Grahame Hardie (University of Dundee, Scotland, United Kingdom) examined whether CAMKK2 could also suppress cell growth via effects on AMPK. Recent evidence suggests that AMPK may be more widely downregulated in a number of cancers than previously thought, as phosphorylation of its downstream substrate ACC was attenuated nearly universally in breast cancer. Alternative mechanisms for suppressing AMPK besides mutation of LKB1 were discussed, including inhibitory phosphorylations on LKB1, and potential overexpression of AMPK gamma subunits in tumor cells acting as dominant negatives.How AMPK controls cell growth was the primary focus of a talk by Dr. Reuben Shaw (Salk Institute, La Jolla, CA), which focused on suppression of the aforementioned mTORC1 signaling pathway. AMPK suppresses mTORC1 by direct phosphorylation of both the TSC2 tumor suppressor and the mTORC1 scaffolding subunit raptor, resulting in a metabolic checkpoint on cell cycle progression. As LKB1-deficient tumors exhibit elevated mTORC1 signaling, this suggested rapamycin may be a potential therapeutic. In a mouse model of Peutz-Jeghers syndrome, LKB1± mice develop gastrointestinal hamartomas similar to their human counterparts, and treatment of these mice with rapamycin resulted in dramatic suppression of their tumor burden. Hypoxia inducible factor (HIF)-1α was identified as a target of mTORC1 in these tumors, and its targets involved in glucose metabolism, including the GLUT1 glucose transporter and Hexokinase II, were upregulated. Consistent with increased glucose uptake and glycolysis, hamartomas in the LKB1± mice showed marked accumulation of 18F-deoxyglucose (FDG), which was reversed by rapamycin, as visualized by imaging wild-type and LKB1± mice with positron emission tomography (FDG-PET).In addition to the treatment of LKB1-deficient tumors with mTORC1 inhibitors, a related question is whether agents that activate AMPK will be clinically useful as anticancer therapeutics due to their ability to suppress mTOR and other growth-promoting pathways. Scott Rothbart from the laboratory of Dr. Richard Moran (Virginia Commonwealth University, Richmond, VA) presented results that the widely used antifolate cancer drug pemetrexed, in addition to targeting thymidine synthase, acts on the enzyme aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), which is a folate-dependent enzyme in de novo purine synthesis. Inhibition of AICART results in a buildup of ZMP in pemetrexed-treated cells, which mimics AMP, activating AMPK and resulting in mTOR suppression. It was hypothesized that this effect of pemetrexed on AMPK and mTOR may explain the activity of pemetrexed in lung cancers, which is unusual for antifolate compounds. A physiological inducer of AMPK activity is the adipose-produced cytokine adiponectin. 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Source: Cancer Research
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1992246284