In order for normal cells to functional, they must sense, take up and metabolize nutrients. This is even more crucial for cancers cells, which are under intense metabolic stress. Studies by Otto Warburg almost a century ago identified fundamental differences between normal and cancer cells. Warburg observed that even in the presence of oxygen, tumor cells rely on glycolysis for their ATP production with the concomitant production of lactic acid (Warburg Effect). Although many aspects of the Warburg Effect are correct, we have a much more sophisticated understanding today (Figure 1).
Linking metabolic disease and cancer
The metabolic syndrome represents a collection disorders that increases the risk of developing cardiovascular disease and type II diabetes. Diabetes is a growing epidemic in the US and the developing world as a whole, which is attributed in large part to the significant rise in the obesity component of the metabolic syndrome. It is estimated that more than 2/3 of the US population are obese or overweight. While increasing the risk factors for other metabolic diseases, obesity and diabetes are significant independent risk factors for a number of different cancers. With the increasing diabetes and obesity trends this represents a significant health concern. Our lab is investigating the metabolic pathways that link obesity and diabetes with colorectal and hepatocellular carcinoma.
Chemoprevention of Hepatocellular Carcinoma by targeting cancer metabolism
Patients with type II diabetes have a 2-3 fold increased relative risk of HCC. Therefore diabetics represent a patient population at risk for HCC that can readily be identified. Metformin is a biguanide that has been used for the treatment of type II diabetes andnon alcoholic fatty liver disease (NAFLD). Metformin has an excellent therapeutic index with few side affects being associated with long term treatment. While studies show that diabetes increases the relative risk of HCC, several epidemiological studies show that diabetics taking metformin have a reduced risk of HCC; however, whether metformin was directly responsible was not known. We recently demonstrated that metformin significantly protects against HCC in a rodent model of HCC. Importantly, this effect was in part mediated by inhibition of de novo lipogenesis, a key pathway in cancer metabolism. Current work in our lab is focused on how metformin controls lipogenesis and the chemopreventive role of metformin in models obesity and diabetes. These studies provides a rationale for clinical trials into the efficacy of metformin in HCC in patients that can readily be identified such as diabetics and other pathologies associated with hepatic lipogenesis such as NAFLD and hepatitis.
Transcriptional links between metabolism and cancer.
Transcription factors and transcriptional regulators coordinate a wide array of metabolic pathways. They represent key nodes for targeting fundamental metabolic pathways driving cancers. PGC1-alpha is a transcriptional coactivator that plays a crucial role in nutrient homeostasis and energy metabolism. PGC1-alpha interacts with a variety of transcription factors to coordinate the regulation of key gene expression programs driving metabolic function in diverse tissues such as fat, liver, muscle and brain. In the liver, PGC1-alphacoordinates hepatic glucose output. We show that loss of PGC1-alpha protects against liver and colon cancer (Bhalla et al 2011). Importantly, our data shows that in addition to oxidative metabolism, PGC1-alpha promotes a transcriptional program driving lipogenesis that is responsible in part for the growth promoting effects of PGC1 (Figure 2). Ongoing studies in our lab are defining the mechanism by which PGC1 drives tumor growth and how this connection links PGC1-alpha and cancer with the metabolic syndrome.
Targeting metabolic flux in cancer
While glycolysis is a key metabolic pathway in cancer, it is now appreciated that glycolysis is but one component of cancer metabolism. For many years it was believed that aspects of oxidative metabolism such as TCA cycle and oxidative phosphorylation were reduced in cancer. However, in order for cells to effectively use glucose and glutamine for biosynthetic pathways described above, carbons derived from these nutrients must enter the TCA cycle. Indeed, increased TCA cycle flux is now recognized as an important pathway in cancer. We are currently studying a key regulator of TCA cycle activity that is overexpressed in the livers and colons of diabetics. This enzyme promotes tumor growth and appears to coordinate multiple aspects of tumor metabolism towards anabolic pathways. We are currently investigating the mechanism(s) by which a metabolic enzyme is regulating tumor growth.
Research in our lab is focused in understanding the link between metabolism and cancer. Our lab is taking an integrated approach to understand the links between metabolism and cancer. We use biochemical, molecular, cellular, and genomic approaches, coupled with in vivo studies to define and target metabolic pathways driving cancer growth. In addition, we have several collaborations investigating how these pathways coordinately controlmetabolic flux and play a role in carcinogenesis and tumor growth using stable isotope 13C based tracers and a combination of GC/LC/MS and NMR based approach.
Girnun, G.D. The diverse role of the PPAR³ Coactivator-1 family of transcriptional coactivators. Seminars in Cell and Developmental Biology (Cancer Cell Metabolism Issue) In Press, Epub ahead of print, 2012.
Bhalla, K., Hwang, B., Dewi, R., Twaddel, Goloubeva, O., Wong, K.K., Saxena, N., Biswal, S., Girnun, G.D. Metformin prevents hepatocellular carcinoma by antagonizing hepatic lipogenesis. Cancer Prev. Res. In Press. April 2012
Bhalla, K., Hwang, B.J., Dewi, R., Twaddell, W. Frang, H.B., Vafai, S.B., Vazquez, F., Puigserver, P., Boros, L.G. Girnun, G.D. The metabolic coactivator PGC1¿ promotes tumor growth by coordinating a gene expression program driving de novo fatty acid synthesis. Cancer Res. 71:6888-6889, 2011.
Bhalla, K., Hwang, B., Dewi, R., Ou, L., Mclenithen, J., Pozarzky, E., Twaddel, W., Girnun, G.D. N-Acetyl Farnesyl Cysteine is a novel class of PPAR-alpha ligand with partial and full agonist activity in vitro and in vivo. J. Biol. Chem. 286:41626-41635, 2011
*Girnun, G.D. Chen, L., Silvaggi, J., Drapkin, R., Chirieac, L.R., Padera, R.F., Upadhyay, R., Vafai, S.B., Wiessleder, R., Mahmood, U., Naseri, E., Buckley, S., Li, D., Force, J., McNamara, K., Demetri, G., Spiegelman, B.M., *Wong, K.K. Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin. Cancer Res. 14:6478-6486, 2008. *co-corresponding authors
Arany Z, Foo, S.Y., Ma, Y., Ruas, J.L., Bommi-Reddy, A., Girnun, G.D., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S.M., Baek, K.H., Rosenzweig, A., Spiegelman, B.M. Nature. 451:1008-1012, 2008