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.
- Kou, L., Huang, H., Lin, X., Jiang X., Wang, Y., Luo, Q., Sun, J., Yao, Q., Ganapathy, V., and Chen, R. (2020) Endocytosis of ATB0,+ (SLC6A14)-targeted liposomes for drug delivery and its therapeutic application for pancreatic cancer. Expert Opinion on Drug Delivery (in press).
- Brown, T. P., Battacharjee, P., Ramachandran, S., Sivaprakasam, S., Ristic, B., Sikder, M. O., and Ganapathy, V. (2020) The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene (in press).
- Kou, L., Sun, R., Xiao, S., Cui, X., Sun, J., Ganapathy, V., Yao, Q., and Chen, R. (2020) OCTN2-targeted nanoparticles for oral delivery of paclitaxel: differential impact of the polyethylene glycol linker size on drug delivery in vitro, in situ, and in vivo. Drug Delivery 27: 170-179.
- Brown, T., and Ganapathy, V. (2020) Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacology and Therapeutics (in press).
- Sivaprakasam, S., Ganapathy, P. K., Sikder, M. O. F., Elmassry, M., Ramachandran, S., Kottapalli, K. R., and Ganapathy, V. (2019) Deficiency of dietary fiber in Slc5a8-null mice promotes bacterial dysbiosis and alters colonic epithelial transcriptome towards pro-inflammatory milieu. Canadian Journal of Gastroenterology and Hepatology(in press).
- Ristic, B., Sikder, M. O. F., Bhutia, Y. D., and Ganapathy, V. (2019) Pharmacologic inducers of the uric acid exporter ABCG2 as potential drugs for treatment of gouty arthritis. Asian Journal of Pharmaceutical Sciences (in press).
- Kou, L., Sun, R., Xiao, S., Zheng, Y., Chen, Z., Cai, A., Zheng, H., Yao, Q., Ganapathy, V., and Chen, R. (2019) An ambidextrous approach to disrupt redox balance in tumor cell with increased ROS production and decreased GSH synthesis for cancer therapy. ACS Applied Materials and Interfaces 11: 26722-26730.
- Chaudhary, K., Chilakala, A., Ananth, S., Mandala, A., Veeranan-Karmegam, R., Powell, F., Ganapathy, V., and Gnana-Prakasam, J. (2019) Renal iron accelerates the progression of diabetic nephropathy in HFE knockout mouse model of genetic iron overload. American Journal of Physiology – Renal Physiology (in press).
- Sadeghzadeh, M., Modovan, R. P., Fischer, S., Wenzel, B., Ludwig, F. A., Teodoro, R., Deuther-Conrad, W., Jonnalagadda, S., Jonnalagadda, S. K., Gudelis, E., Sachus, A., Higuchi, K., Ganapathy, V., Mereddy, V. R., Drewes, L. R., and Brust, P. (2019) Development and radiosynthesis of the first 18F-labeled inhibitor of monocarboxylate transporters (MCTs). Journal of Labelled Compounds and Radiopharmaceuticals 62: 411-424.
- Ogura, J., Sato, T., Higuchi, K., Bhutia, Y. D., Babu, E., Masuda, M., Miyauchi, S., Rueda, R., Pereira, S. L., and Ganapathy, V. (2019) Transport mechanisms for the nutritional supplement β-hydroxy-β-methylbutyrate (HMB) in mammalian cells. Pharmaceutical Research 36: 84.
- Sugio, K., Inoda, D., Masuda, M., Azumaya, I., Sasaki, S., Shimono, K., Ganapathy, V., and Miyauchi, S. (2019) Transport of 2,4-dichloro phenoxyacetic acid by human Na+-coupled monocarboxylate transporter 1 (hSMCT1, SLC5A8). Drug Metabolism and Pharmacokinetics 34: 95-103.
- Janovick, J. A., Spicer, T. P., Bannister, T. D., Smith, E., Ganapathy, V., and Scampavia, L. (2018) Chemical validation and optimization of pharmacoperones targeting vasopressin type 2 receptor mutant. Biochemical Journal 475: 2941-2953.
- Shekhawat, P. S., Sonne, S., Matern, D., and Ganapathy, V. (2018) Embryonic lethality in mice due to carnitine transporter OCTN2 defect and placental carnitine deficiency. Placenta 69: 71-73.
- Kou, L., Sun, R., Ganapathy, V., Yao, Q., and Chen, R. (2018) Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5). Expert Opinion in Therapeutic Targets 22: 715-726.
- Bhatt, B., Zeng, P., Zhu, H., Sivapraksasm, S., Li, S., Xiao, H., Dong, L., Shiao, P., Kolhe, R., Patel, N., Li, H., Levy-Barcowski, D., Ganapathy, V., and Singh, N. (2018) Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation. Journal of Immunology 200: 2905-2914.
- Mycielska, M., Dettmer-Wilde, K., Rummele, P., Schmidt, K., Prehn, C., Milenkovic, V., Jagla, W., Madej, W., Lantow, M., Schladt, M., Cecil, A., Kohl, G., Eggenhofer, E., Wachsmuth, C., Ganapathy, V., Schlitt, H., Kunzelmann, K., Ziegler, C., Wetzel, C., Gaumann, A., Lang, S., Adamski, J., Oefner, P., and Geissler, E. (2018) Extracellular citrate affects critical elements of cancer cell metabolism and supports cancer development in vivo. Cancer Research 78: 2513-2523.
- Chaudhary, K., Promsote, W., Ananth, S., Veeranan-Karmegam, R., Tawfik, A., Arjunan, P., Martin, P. M., Smith, S. B., Thangaraju, M., Kisselev, O., Ganapathy, V., and Gnana-Prakasam, J. P. (2018) Iron overload accelerates the progression of diabetic retinopathy in association with increased retinal renin expression. Scientific Reports 8: 3025.
- Kou, L., Bhutia, Y. D., Yao, Q., He, Z., Sun, J., and Ganapathy, V. (2018) Transporter-guided delivery of nanoparticles to improve drug permeation across cellular barriers and durg exposure to selective cell types. Frontiers in Pharmacology 9: 27.
- Ranganathan, P., Shanmugam, A., Swafford, D., Suryawanshi, A., Bhattacharjee, P., Hussein, M., Koni, P. A., Prasad, P. D., Kurago, Z. B., Thangaraju, M., Ganapathy, V., and Santhakumar, M. (2018) GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. Journal of Immunology200: 1781-1789.
- Sikder, M. O. F., Yang, S., Ganapathy, V., and Bhutia, Y. D. (2017) The Na+/Cl- -coupled, broad-specific, amino acid transporter SLC6A14 (ATB0,+): Emerging roles in multiple diseases and therapeutic potential for treatment and diagnosis. AAPS Journal 20: 12.
- Kopel, J., Bhutia, Y. D., Ramachandran, S., Lawrence, J. J., Neugebauer, V., and Ganapathy, V. (2017) Tooth hypoplasia for differential diagnosis of childhood epilepsy associated with SLC13A5 mutations. International Journal of Neurological Disorders 1: 33-37.
- Bhutia, Y. D., and Ganapathy, V. (2018) Digestion and absorption of dietary carbohydrate, protein, and fat. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Dignosis/Management (ed. Lawrence, B. J.), 11th Edition, in press.
- Bhutia, Y. D., and Ganapathy, V. (2018) Protein digestion and absorption. In: Physiology of the Gastrointestinal Tract (ed. Said, H. M.), 6th Edition, pp. 1063-1086. Elsevier.
- 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.