Monday, May 7, 2012 (past event)

The University of Chicago
Max Palevsky Cinema,
Ida Noyes Hall (Directions)
1212 E. 59th St
Chicago, IL


Schedule (PDF Download)

(Registration 7:30am  Symposium 8:15-5:00pm)

Craig Thompson M.D.
Memorial Sloan Kettering Cancer Center
“Cancer Metabolism and Epigenetics”
Kun Liang Guan Ph.D.
University of California, San Diego
“Acetylation in Metabolism Regulation”
Wei Gu Ph.D.
Columbia University
“Tumor Suppression in the Absence of p53-Mediated Cell Cycle Arrest, Apoptosis, and Senescence”
M. Celeste Simon Ph.D.
UPenn Perelman School of Medicine
“HIFs, Hypoxia, and Cancer Metabolism”
Barbara Kahn M.D.
Harvard Medical School
“A Novel Inhibitory AMPK Kinase Involved in Nutrient and Hormonal Regulation of AMPK: implications for cancer"
Navdeep S. Chandel Ph.D.
Northwestern University Feinberg School of Medicine
“Mitochondria and Cancer”
Toren Finkel M.D., Ph.D.
National Institutes of Health
“Intersections Between Cancer and Metabolism:  Two Short Stories”
C. Ronald Kahn M.D.
Joslin Diabetes Center, Harvard Medical School
“The Yin and the Yang of Insulin/IGF-1 Signaling – Its Relevance to Diabetes and Cancer”



Craig Thompson M.D. (go to top)

Our interest in studying connections between metabolism and the regulation of epigenetic remodeling of chromatin began with the discovery that the aerobic glycolysis (Warburg effect) exhibited in many tumor cells was accompanied by elevations in cytoplasmic acetyl-CoA levels. The rate of glycolytic flux could contribute to a 1-2 log increase in cytosolic acetyl-CoA levels and this had a generalized influence on histone acetylation and the expression of a wide variety of genes involved in signal transduction or metabolic regulation.  These data have led to the realization that the activity of the GNAT-family of protein acetyl transferases is regulated in part by variations in cytoplasmic acetyl-CoA levels.  Constitutive activation of aerobic glycolysis through activating mutations in PI3K or the loss of PTEN can lead to a positive feedback loop that enhances cells’ ability to effectively use glucose as a metabolic substrate to fuel cell growth through lipid and nucleotide synthesis.  This feed-forward loop can enhance cellular resistance to apoptosis and promote cell growth and division, thus phenotyping two of the cardinal properties of transformed cells.  However, studies carried out in several differentiation systems suggested that the metabolic influence on histone acetylation levels was not accompanied by significant changes in the ability of cells to differentiate.  In contrast, others were finding clear association between changes in DNA/histone methylation and cellular differentiation.  

Altered DNA methylation has now been established as a hallmark of acute leukemia and yet very little is known concerning the mechanisms through which this occurs. Last year, in collaboration with others, we found that neomorphic mutations of the citrate metabolism genes IDH1 and IDH2 induce DNA hypermethylation and impair differentiation in hematopoietic cells. IDH mutations create a block to DNA and histone demethylation as a result of the production of 2-hydroxyglutarate (2HG). 2HG acts as a competitive inhibitor of α-ketoglutarate-dependent enzymes. The epigenetic effects of 2HG are caused in part though inhibition of TET2, a DNA demethylase enzyme also mutated in leukemia. IDH 1/2- and TET2-mutant primary AML cells displayed a similar defect in epigenetic programming consisting of global hypermethylation and a gene-specific methylation signature. This work identifies IDH1/2- and TET2-mutant leukemias as a biologically distinct disease subtype, and links cancer metabolism with epigenetic control of gene expression. The implications of this work and the identification of additional metabolic genes involved in epigenetic deregulation of cancer will be discussed.

Kun Liang Guan Ph.D. (go to top)

Protein lysine acetylation has emerged as a key posttranslational modification in cellular regulation.  We have shown that lysine acetylation is a prevailing form of modification in intermediate metabolic enzymes.  Virtually every enzyme in glycolysis, gluconeogenesis, TCA cycle, urea cycle, fatty acid metabolism, and glycogen metabolism are found to be acetylated in human liver tissue.  Furthermore, metabolic fuels, such as glucose, amino acids, and fatty acids, regulate acetylation status of metabolic enzymes.  We show that acetylation activates malate dehydrogenase in the TCA cycle, inhibits ASL in the urea cycle, promotes dephosphorylation of glycogen phosphorylase in glycogen metabolism, and destabilizes PEPCK1 in gluconeogenesis and PKM2 in glycolysis. Our findings reveal a previously general role of acetylation in cellular metabolic regulation.

Wei Gu Ph.D. (go to top)

Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation.  Nevertheless, it remains unclear whether they are rate-limiting steps in tumor suppression.  We have generated p53 mutant mice that lack p53-mediated cell-cycle arrest, apoptosis and senescence.   Surprisingly, unlike p53-null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in these p53 mutant animals. Our results suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for tumor suppression.

M. Celeste Simon Ph.D. (go to top)

Oxygen (O2) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O2 availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIFa subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1a (FIN1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway.

Barbara Kahn M.D. (go to top)

A novel inhibitory AMPK Kinase involved in nutrient and hormonal regulation of AMPK: implications for cancer.

Yossi Dagon, Elizabeth Hur, Bin Zheng, Lewis C. Cantley and Barbara B. Kahn Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA USA

AMPK is an evolutionarily conserved cellular energy sensor which also functions at the whole body level to regulate metabolism and energy balance.  AMPK activity is reduced in some tumors and AMPK activators appear to have therapeutic effects.  Leptin is a master regulator of neuroendocrine, metabolic, vascular, sympathetic and immune function.  Some critical effects of leptin are mediated through the AMPK pathway.  In particular, leptin’s effects on food intake and body weight depend on inhibition of AMPK in the hypothalamus.  We sought to determine the signaling events responsible for inhibition of AMPK activity since they might also yield new opportunities for cancer treatment.  We found a novel serine phosphorylation site on the AMPK alpha 2 catalytic subunit that mediates leptin’s inhibitory effects.  Investigation of the upstream kinase cascade that phosphorylates AMPK on this site revealed convergence of the AMPK and PI3 kinase/Akt signaling pathways.  Bioinformatic analysis led to identification of a novel, inhibitory AMPK kinase that is critical for leptin action.  Since this upstream kinase is known to regulate cell growth and development, it may play a role in the AMPK inhibition that is present under other circumstances including neoplastic growth.  This pathway and the novel serine phosphorylation site on AMPK could provide new therapeutic strategies for both metabolic disease and cancer.

Navdeep S. Chandel Ph.D. (go to top)

In the 1920s, Otto Warburg observed that tumor slices have elevated levels of glucose consumption and high lactate production in the presence of ample oxygen (termed the Warburg effect).  He later postulated that cancer originates from irreversible injury to respirationfollowed by an increase in glycolysis to replace the ATP lost from defective oxidative phosphorylation.  According to Warburg, this metabolic shift from oxidative phosphorylation to glycolysis converts highly differentiated cells into undifferentiated cells that proliferate as cancer cells.  Although the observation that tumor cells exhibit high levels of aerobic glycolysis has been corroborated, the role of mitochondria in tumor cells has been contentious. While multiple investigators have demonstrated that mitochondria are indeed functional in most tumor cells, some argue that a decrease in mitochondrial metabolism and respiratory rate is essential for tumor cell proliferation. Other investigators have argued that oncogenes induce an increase in mitochondrial metabolism.  One attractive model of tumor cell metabolism is that oncogene induced transformation depends on elevated glycolysis for the diversion of glycolytic intermediates to pathways that generate lipids, nucleotides and amino acids. The TCA cycle is also critical for the generation of ATP, lipids, nucleotides, amino acids, NADPH and ROS. Interestingly, tumors with defective mitochondria are able to generate ROS and undergo reductive carboxylation to generate the necessary metabolites required for cell proliferation. Thus, mitochondria are critical for cancer growth even when they are not generating ATP. 

Toren Finkel M.D., Ph.D. (go to top)

In my presentation, I will discuss results from two ongoing projects in my laboratory. In the first part of the presentation, I will present data on the intersection of autophagy with the tumor suppressor p53. Autophagy is a process in which damaged proteins and organelles are recycled via double membrane structures known as autophagosomes. In order to maintain homeostasis, there is always a certain level of basal autophagy occurring in cells. Certain stresses, most notably nutritional stresses such as starvation, result in a marked induction of autophagic flux. I will demonstrate that under nutrient stress conditions, cells with impaired autophagy manifest an unexpected dysregulation of p53 activity. I will provide both biochemical and genetic data to hopefully demonstrate the physiological importance of this dysregulation. In the second half, I will provide a metabolomic analysis of oncogene-induced senescence. Our analysis allows for the resolution of approximately 300 intracellular metabolites. This analysis will demonstrate some of the specific metabolic alterations that occur in Ras-induced senescence.  These data also provide insight into how it may be possible to resolve different forms of senescence based on their metabolic profile as well as ways one could potentially combat the harmful effects of senescence via targeted metabolic intervention. 

C. Ronald Kahn M.D. (go to top)

The Yin and the Yang of Insulin/IGF-1 Signaling – Its Relevance to Diabetes and Cancer

In the 90 years since the discovery of insulin, much has been learned about the insulin signaling network.  In general, insulin has potent and positive effects on metabolism, whereas insulin resistance is associated with a wide range of disorders, including type 2 diabetes, obesity, and the metabolic syndrome.  Individuals with insulin resistance and metabolic syndrome are also at increased risk for cancer.  Over the past few years, as we have studied the insulin signaling network, two pathways have been identified which may contribute to this risk.  At the level of the receptor, insulin and IGF-1 are important anti-apoptotic hormones.  Using preadipocytes as a model system, we find that whereas cells with both receptors intact, or cells lacking either the insulin receptor (IR) or the IGF-1 receptor (IGF1R), show normal apoptotoic responses to serum withdrawal, double knockout (DKO) cells, i.e. cells lacking both insulin and IGF-1 receptors, show remarkable resistance to apoptosis under a variety of stress conditions. Resistance to apoptosis is observed in both the extrinsic pathway induced by activation of death-inducing receptors, such as TNF and the intrinsic pathway induced by growth factor deprivation, DNA damage or oxidative stress. The apoptosis resistance in DKO cells iis due to decreased levels of the pro-apoptotic protein Bax and an increase in the anti-apoptotic proteins Bcl2 and Flip, which occurred primarily through post-transcriptional control of expression. Thus, the insulin and IGF-1 receptors have a unique, bidirectional roles in the control of cell survival.  Insulin and IGF-1 binding to their receptors blocks apoptosis, whereas unliganded insulin and IGF-1 receptors provide a permissive effect in cell death.

Downstream of the receptor, class Ia phosphoinositide (PI) 3-kinase is a central mediator of growth factor signaling and the metabolic actions of insulin. The enzyme exists as a heterodimer composed of a catalytic (p110) and regulatory (p85) subunit. Recently we have shown that the p85 subunit of PI3K has unique insulin-independent actions which may also contribute to cancer.  Thus,  p85ainteracts with X-box binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an ER stress-dependent manner. Cell lines with genetic ablation or shRNA-mediated knockdown of p85aexhibit dramatic alterations in the UPR including reduced ER stress-dependent accumulation of nuclear XBP-1, decreased induction of UPR target genes and increased rates of apoptosis. Mice with targeted deletion of p85ain liver (L-p85a-/-) also display an attenuated UPR following tunicamycin administration with reduced nuclear accumulation of XBP-1 and ATF6aand a decreased induction of UPR target-genes. More strikingly, mice with a liver-specific deletion of p85adevelop aggressive hepatocellular carcinoma by 14-16 months of age, with pulmonary metastases in 60% of the mice with tumors.  These liver tumors are characterized by a marked upregulation of Akt phosphorylation, that correlates with an elevation in phosphatidylinositol-3,4,5-trisphosphate and decreased expression of PTEN.  These data indicate that, in addition to its more recognized role as a component of the PI3K signaling pathway, the p85 subunit of PI3K may play a novel role as a mediator of the UPR and act as tumor suppressor in the liver and possibly other tissues.  The phosphoinositide 3-kinase (PI3K) pathway plays a critical role in tumorigenesis, and the p85 subunit of PI 3-kinase is a bi-directional regulator of the pathway.