Vadivel Ganapathy, Ph.D.
Cancer biology; development of novel anticancer drugs; interaction between gut microbiome and the host; structure and function of the retina in health and disease.
Cancer biology and development of novel anticancer drugs.
Tumor cells grow faster than normal cells and therefore have an increased demand for nutrients. This increased demand is met with via upregulation of selective transporters in the plasma membrane. Such nutrient transporters that are selectively upregulated in cancer represent novel drug targets because blockade of these transporters would lead to starvation in tumor cells, thus interfering with their growth and proliferation. We are particularly focusing on the transporters for amino acids because most cancers are “addicted” to the amino acid glutamine. The current focus is on the amino acid transporter SLC6A14 that is upregulated in colon cancer, pancreatic cancer, cervical cancer, and some subtypes of breast cancer. We have identified small molecules that block this transporter and show efficacy in cancer treatment in pre-clinical animal models, strongly suggesting the therapeutic potential of this transporter as a target for development of a novel class of anticancer drugs.
Hemochromatosis is a widely prevalent genetic disease of excessive iron accumulation. Most people have not heard about this disease even though it occurs in 1 in 250 people in this country. Patients born with this disease lead a normal life almost for 50-60 years after which almost every organ in the body starts failing due to the damage caused by excessive iron accumulation. Our research has now indicated that this disease is a driver of cancer growth and metastasis in colon, lung, and prostate. Delineation of the molecular events that underlie the promotion of cancer growth and metastasis by excessive iron in this disease is one of the focuses in our laboratory.
Interaction between gut microbiome and the host and its relevance to colon health.
Our intestinal tract, particularly the colon, is the home for trillions of bacteria. These are not pathogenic but actually beneficial to the host. These bacteria feed on dietary fiber and generate a variety of metabolites that are believed to mediate the beneficial effects of the bacteria and fiber on the host. One important class of these bacterial metabolites is short-chain fatty acids, which include acetate, propionate, and butyrate. Our laboratory has identified a transporter for these metabolites in colonic epithelial cells (SLC5A8) that is obligatory for the beneficial effects of these metabolites. Deletion of this transporter in mice increases inflammation and carcinogenesis in colon under various experimental conditions. We also have identified two G-protein-coupled receptors, GPR109A for butyrate and GPR43 for acetate, propionate and butyrate, that are expressed in the colonic epithelium and mucosal immune cells. Deletion of either of these two receptors in mice increases the risk of colonic inflammation and colon cancer. While the transporter SLC5A8 is necessary for the entry and intracellular actions of short-chain fatty acids in the colon cells, the receptors GPR109A and GPR43 are necessary for the extracellular actions of these bacterial metabolites. Interrogation of these three proteins in terms of their role in the communication between gut microbiome and the host and also the relevance of dietary fiber in the process is an active project ongoing in the laboratory.
Structure and function of retina in health and disease.
Retina is vital for visual function, and its structure and function are altered in many diseases such as diabetes and age-related macular degeneration. Many of these diseases also are associated with increased accumulation of iron in the retina. Our laboratory is involved in figuring out how the iron status in the retina is regulated and maintained and how disruption of the retinal iron status contributes to damage observed in the structure and function of the retina in various diseases.
- Bhutia, Y. D., and Ganapathy, V. (2015) Short, but smart: SCFAs train T cells in the gut to fight autoimmunity in the brain. Immunity 43:629-631. PubMed
- Gurav, A., Sivaparakasam, S., Bhutia, Y. D., Boettger, T., Singh, N., and Ganapathy, V. (2015) Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumor suppressor in colon that protects against colitis and colon cancer under low-fiber dietary conditions. Biochemical Journal 469: 267-278. PubMed
- Babu, E., Bhutia, Y. D., Ramachandran, S., Gnanaprakasam, J. P., Prasad, P. D., Thangaraju, M., and Ganapathy, V. (2015) Deletion of the amino acid transporter Slc6a14 suppresses tumor growth in spontaneous mouse models of breast cancer. Biochemical Journal 469: 17-23. (Accelerated Publication) PubMed
- Bhutia, Y. D., Babu, E., Ramachandran, S., and Ganapathy, V. (2015) Amino acid transporters in cancer and their relevance to “glutamine addiction”: Novel targets for the design of a new class of anticancer drugs. Cancer Research 75: 1782-1788. Invited Review. PubMed
- Gopal, E., Babu, E., Ramachandran, S., Bhutia, Y. D., Prasad, P. D., and Ganapathy, V. (2015) Species-specific influence of lithium on the activity of SLC13A5 (NaCT): Lithium-induced activation is specific for the transporter in primates. Journal of Pharmacology and Experimental Therapeutics 353: 17-26. PubMed
- Bhutia, Y. D., Babu, E., and Ganapathy, V. (2014) Interferon-γ induces a tryptophan-selective amino acid transporter in human colonic epithelial cells and mouse dendritic cells. Biochimica et Biophysica Acta 1848: 453-462. PubMed
- Bhutia, Y. D., Babu, E., Prasad, P. D., and Ganapathy, V. (2014) The amino acid transporter SLC6A14 in cancer and its potential use in chemotherapy. Asian Journal of Pharmaceutical Sciences (doi.org/10.106/j/ajps.2014.04.004).
- Gnana-Prakasam, J. P., Baldowski, R. B., Ananth, S., Martin, P. M., Smith, S. B., and Ganapathy, V. (2014) Expression of the serine protease matriptase-2 (Tmprss6) in retina and its role in retinal iron homeostasis. Molecular Vision 20: 561-574. PubMed
- Ananth, S., Gnana-Prakasam, J. P., Bhutia, Y. D., Veeranan-Karmegam, V., Martin, P. M., Smith, S. B., and Ganapathy, V. (2014) Regulation of the cholesterol efflux transporters ABCA1 and ABCG1 in retina in hemochromatosis and by the endogenous siderophore 2,5-dihydroxybenzoic acid. Biochimica et Biophysica Acta 1842: 603-612. PubMed
- Elangovan, S., Pathania, R., Ramachandran, S., Ananth, S., Padia, R. N., Lan, L., Singh, N., Martin, P. M., Hawthorn, L., Prasad, P. D., Ganapathy, V., and Thangaraju, M. (2014) The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival. Cancer Research 74: 166-178. PubMed
- Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., Thangaraju, M., Prasad, P. D., Manicassamy, S., Munn, D. H., Lee, J. R., Offermanns, S., and Ganapathy, V. (2014) Regulation of colonic inflammation and carcinogenesis by Gpr109a, a G-protein-coupled receptor for niacin and the commensal metabolite butyrate. Immunity 40: 128-139. PubMed
- Peden, A. S., Mac, P., Fei, Y. J., Castro, C., Jiang, G., Murfitt, K. J., Miska, E. A., Griffin, J. L., Ganapathy, V., and Jorgensen, E. M. (2013) Betaine acts on a ligand-gated iron channel in the nervous system of the nematode C. elegans. Nature Neuroscience 16: 1794-1801. PubMed
- Ganapathy, V., Thangaraju, M., Prasad, P. D., Martin, P. M., and Singh, N. (2013) Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Current Opinion in Pharmacology 13: 869-874. PubMed
- Elangovan, S., Pathania, R., Ramachandran, S., Ananth, S., Padia, R. N., Srinivas, S. R., Babu, E., Howthorn, L., Schoenlein, P. V., Boettger, T., Smith, S. B., Prasad, P. D., Ganapathy, V., and Thangaraju, M. (2013) Molecular mechanism of SLC5A8-inactivation in breast cancer. Molecular and Cellular Biology 33: 3920-3935. PubMed
- Sonne, S. R., Bhalla, V. K., Barman, S. A., White, R. E., Zhu, S., Newman, T. M., Prasad, P. D., Smith, S. B., Offermanns, S., and Ganapathy, V. (2013) Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth. Bochimica et Biophysica Acta 1832: 1149-1158. PubMed
- Coothankandaswamy, V., Elangovan, S., Singh, N., Prasad, P. D., Thangaraju, M., and Ganapathy, V. (2013) The plasma membrane transporter SLC5A8 suppresses tumor progression through depletion of survivin without involving its transport function. Biochemical Journal 450: 169-178. PubMed
- Shekhawat, P., Sonne, S. R., Carter, A. L., Matern, D., and Ganapathy, V. (2013) Enzymes involved in L-carnitine biosynthesis are expressed by intestinal enterocytes in mice: Implications for gut health. Journal of Crohn’s and Colitis 7: e197-205. PubMed
- Gnana-Prakasam, J. P., Veeranan-Karmegam, R., Coothankandaswamy, V., Reddy, S. K., Martin, P. M., Thangaraju, M., Smith, S. B., and Ganapathy, V. (2013) Loss of Hfe leads to progression of tumor phenotype in primary retinal pigment epithelial cells. Investigative Ophthalmology and Visual Science 54: 63-71. PubMed
- Fulzele, S., Chothe, P., Sangani, R., Chutkan, N., Hamrick, M., Battacharya, M., Prasad, P. D., Zakhary, I., Bowser, M., Isales, C., and Ganapathy, V. (2013) Sodium-dependent vitamin C transporter SVCT2: Expression and function in bone marrow stromal cells and in osteogenesis. Stem Cell Research 10: 36-47. PubMed
- Bhutia, Y. D., and Ganapathy, V. (2015) A novel tryptophan-selective amino acid transporter that is functionally coupled to IDO1-dependent signaling pathways. In: New Developments in Tryptophan Research (edited by V. Hayes), pp. xx – xx. Nova Science Publishers.
- Mao, Q., Ganapathy, V., and Unadkat, J. D. (2014) Drug transport in the placenta. In: Drug Transporters: Molecular Characterization and Role in Drug Disposition (Eds., You, G, and Morris, M. E. ), Second Edition, pp. 341-353. John Wiley & Sons, New Jersey.
- Ganapathy, V., Prasad, P. D., Thangaraju, M., Martin, P. M., and Singh, N. (2014) Butyrate-mediated protection against colonic inflammation and colon carcinogenesis: Role of butyrate transporters and butyrate receptors. In: Butyrate: Food Sources, Functions and Health Benefits (Ed., Li, C.), pp. 157-176. Nova Science Publishers, Inc., Hauppauge, New York.
- Ganapathy, V. (2012) Protein digestion and absorption. In: Physiology of the Gastrointestinal Tract (ed. Johnson, L.R.), 5th Edition, pp., 1595-1623. Elsevier.
- Ganapathy, V. Ganapathy, M.E., and Leibach, F.H. (2008) Protein digestion and assimilation. In: Textbook of Gastroenterology (eds., Yamada, T., Alpers, D.H., Kalloo, A.N., Kaplowitz, N., Owyang, C., and Powell, D.W.), 5th edition, pp. 464-477. Blackwell Publishing.