1120 15th Street CB 2740B Augusta, GA 30912 Office: (706) 721-7652 E-mail: vganapat@georgiahealth.edu Developmental Therapeutics; Multidisciplinary Gastrointestinal, Gynecologic Oncology Teams; Molecular Biologist Research interests: Nutrient transport in intestine, kidney and placenta; genetic disorders of membrane transport; molecular biology of membrane transporters

Ganapathy, Vadivel, Ph.D.

Dr. Vadivel Ganapathy, biochemist at GHSU in his officeDepartment Chair, Graduate Program in Biochemistry and Cancer Biology
Leader, Signaling & Angiogenesis Program
GRU Cancer Center
Regents’ Professor of Biochemistry and Molecular Biology
Professor of Physiology, Surgery and Obstetrics and Gynecology

1120 15th Street, CN 1177A
Phone: (706) 721-7652
VGANAPAT@ gru.edu

IFL Link | PubMed Link

 

Professional Overview

Vadivel Ganapathy, Ph.D. is the Department Chair and Regents’ Professor of Biochemistry and Molecular Biology at GHSU. He is also a Professor in the Departments of Physiology, Surgery, Obstetrics and Gynecology, and in the College of Graduate Studies.  An example of inter-professional research and collaboration, Dr. Ganapathy currently has four major projects underway related to colon and breast cancers.

Current Research

Project 1 (The niacin/butyrate receptor GPR109A is a tumor suppressor in colon and serves as a link between colonic bacteria and the host) focuses on the role of the newly identified tumor suppressor GPR109A in colon cancer. GPR109A is a G-protein-coupled receptor for which the physiological agonist is b-hydroxybutyrate and the pharmacological agonist is the B-complex vitamin niacin. Dr. Ganapathy’s laboratory recently discovered that the receptor is expressed in the luminal membrane colon epithelial cells and that the bacterial fermentation product butyrate serves as the physiological agonist for the receptor. GPR109A provides a molecular link between colonic bacteria and the host to mediate the beneficial effects of dietary fiber/colonic bacteria on the host. While rodents express only GPR109A, humans express not only GPR109A but also a closely related isoform GPR109B. The relevance of the isoform to colon cancer is unknown. Dr. Ganapathy is studying the role of this interesting isoform in colon cancer and comparing its biology with that of GPR109A.

Project 2 (Amino acid transporters as drug targets for treatment of cancer) focuses on amino acid transporters in breast cancer and colon cancer. One amino acid transporter, known as SLC6A14, is up-regulated in estrogen receptor-positive breast cancer and in colon cancer. Studies in Dr. Ganapathy’s laboratory have already shown that pharmacological blockade or shRNA-mediated silencing of the transporter suppresses tumor growth in several models of ER-positive breast and colon cancer. Another amino acid transporter, known as SLC38A5, is selectively up-regulated in triple-negative breast cancer. The goal of this project is to delineate the role of this transporter in the progression of triple-negative breast cancer and to examine the therapeutic potential of SLC38A5 for selective and for targeted treatment of triple-negative breast cancer.

Project 3 (The tumor-suppressive function of the pyruvate/butyrate transporter SLC5A8 and its potential as a drug target for cancer treatment) studies the role of a transporter, known as SLC5A8, in colon cancer. SLC5A8 is a transporter for the bacterial fermentation product butyrate and is expressed on the luminal membrane of colon epithelial cells. This transporter is silenced in colon cancer by DNA methylation. Interestingly, this transporter is dispensable when dietary fiber intake is optimal, but becomes obligatory only when dietary fiber intake is not sufficient. This appears logical based on the kinetics of the transporter for butyrate. Dr. Ganapathy’s laboratory is studying the relevance of dietary fiber content to the biology of SLC5A8, the transporter’s tumor-suppressive function, molecular mechanisms underlying the tumor-associated silencing of the transporter, and strategies for re-activating the expression of the transporter in colon cancer for therapeutic purposes.

Project 4 (Homocysteine is an oncometabolite that promotes breast cancer growth and progression) is related to the potential association between homocysteine and breast cancer. The hypothesis in this project is that homocysteine is an “oncometabolite,” which promotes the progression and metastasis of breast cancer. The focus of the project is to employ mouse models of hyperhomocysteinemia to elucidate the relevance of elevated levels of homocysteine to the progression and metastasis of breast cancer. This project has direct clinical relevance to humans because elevation of circulating levels of homocysteine is quite prevalent in the US population due to mutations in the gene coding for the enzyme methylene tetrahydrofolate reductase. It is likely that outcomes of breast cancer, in terms of the aggressiveness of tumor growth as well as metastasis, might be significantly facilitated in individuals with hyperhomocysteinemia. These findings have substantial clinical and therapeutic impact in breast cancer therapy because if the role of homocysteine in breast cancer growth is established, strategies to decrease circulating levels of homocysteine (e.g., nutritional supplementation of methytetrahydrofolate) would benefit the breast cancer patients.

 

Grants (selected)

  • National Cancer Institute: “Starve the Tumor Cells to Death: SLC6A14 as a Drug Target for Colon Cancer” 2010-2012, V. Ganapathy, PI
  • National Eye Institute: “Retinal Iron Homeostatis in Health and Disease,” 2010-2014, V. Ganapathy, PI
  • National Health Institute: “Tumor-Suppressive Function of SLC5A8 in Mammary Gland and its Relevance to Breast Cancer.”  2008-2013, V. Ganapathy, co-I
  • Department of Defense: “SLC5A8-Mediated Switching of STAT3 from a Pro-Oncogenic Signal into a Pro-Apoptotic Signal in Breast Cancer.” 2008-2011, V. Ganapathy, co-I
  • Pfizer Pharmaceuticals: “Molecular Biology of Membrane Transporters ” 2002-2012

Grant information is updated quarterly.

 

Publications (selected)

editorial board member:

  • Pharmaceutical Research

editorial reviewer:

  • American Journal of Physiology
  • Metabolism
  • Pediatric Research
  • Journal of Receptor Research
  • Biochimica et Biophysica Acta
  • Placenta
  • Biochemistry
  • Journal of Biological Chemistry
  • Journal of Physiology
  • American Journal of Obstetrics and Gynecology
  • Life Sciences
  • FEBS Journal
  • Canadian Journal of Pharmacy and Pharmacology
  • Molecular Pharmacology
  • Journal of Ocular Pharmacology and Therapeutics
  • Molecular Pharmaceutics
  • Experimental Physiology
  • Current Eye Research
  • Cellular and Molecular Life Sciences
  • Investigative Ophthalmology and Visual Science
  • Pharmaceutical Research
  • Journal of Pharmacology and Experimental Therapeutics
  • Physiology
  • Journal of Experimental Biology
  • Journal of Neurochemistry

Edwards N, Anderson CM, Gatfield KM, Jevons MP, Ganapathy V, Thwaites DT. Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2). Biochim Biophys Acta. 2011 Jan;1808(1):260-70.

Ha Y, Dun Y, Thangaraju M, Duplantier JN, Dong Z, Liu K, Ganapathy V, Smith SB. Sigma receptor 1 modulates ER stress in retinal neurons. Invest Ophthalmol Vis Sci. 2011 Jan 25;52(1):527-40. Print 2011.

Zimmerman M, Yang D, Hu X, Liu F, Singh N, Browning D, Ganapathy V, Chandler P, Choubey D, Abrams SI, Liu K. IFN-γ upregulates survivin and Ifi202 expression to induce survival and proliferation of tumor-specific T cells. PLoS One. 2010 Nov 22;5(11):e14076.

Ganapathy V. Drugs of abuse and human placenta. Life Sci. 2010 Oct 15. [Epub ahead of print]

Li Y, Zhang M, Chen H, Dong Z, Ganapathy V, Thangaraju M, Huang S. Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis. Cancer Res. 2010 Oct 15;70(20):7894-904.

Kommareddi PK, Nair TS, Thang LV, Galano MM, Babu E, Ganapathy V, Kanazawa T, McHugh JB, Carey TE. Isoforms, expression, glycosylation, and tissue distribution of CTL2/SLC44A2. Protein J. 2010 Aug;29(6):417-26.

Singh N, Thangaraju M, Prasad PD, Martin PM, Lambert NA, Boettger T, Offermanns S, Ganapathy V. Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J Biol Chem. 2010 Sep 3;285(36):27601-8.

Fan X, Ross DD, Arakawa H, Ganapathy V, Tamai I, Nakanishi T. Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors. Biochem Pharmacol. 2010 Sep 15;80(6):811-8.

Bozard BR, Ganapathy P, Duplantier JN, Mysona B, Ha Y, Roon P, Smith R, Goldman ID, Prasad PD, Martin PM, Ganapathy V, Smith SB. Molecular and biochemical characterization of folate transport proteins in retinal Muller cells. Invest Ophthalmol Vis Sci. 2010 Jun;51(6):3226-35.

Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, Reiss M. Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer. 2010 May 26;9:122.

Mazurek MP, Prasad PD, Gopal E, Fraser SP, Bolt L, Rizaner N, Palmer CP, Foster CS, Palmieri F, Ganapathy V, St hmer W, Djamgoz MB, Mycielska ME. Molecular origin of plasma membrane citrate transporter in human prostate epithelial cells. EMBO Rep. 2010 Jun;11(6):431-7. Epub 2010 May 7.

Gnana-Prakasam JP, Martin PM, Smith SB, Ganapathy V. Expression and function of iron-regulatory proteins in retina. IUBMB Life. 2010 May;62(5):363-70. Review.

Becker HM, Mohebbi N, Perna A, Ganapathy V, Capasso G, Wagner CA. Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis. Am J Physiol Renal Physiol. 2010 Jul;299(1):F141-54.

Kwon IK, Wang R, Thangaraju M, Shuang H, Liu K, Dashwood R, Dulin N, Ganapathy V, Browning DD. PKG inhibits TCF signaling in colon cancer cells by blocking beta-catenin expression and activating FOXO4. Oncogene. 2010 Jun 10;29(23):3423-34.

Miyauchi S, Gopal E, Babu E, Srinivas SR, Kubo Y, Umapathy NS, Thakkar SV, Ganapathy V, Prasad PD. Sodium-coupled electrogenic transport of pyroglutamate (5-oxoproline) via SLC5A8, a monocarboxylate transporter. Biochim Biophys Acta. 2010 Jun;1798(6):1164-71.

Ananth S, Zhuang L, Gopal E, Itagaki S, Ellappan B, Smith SB, Ganapathy V, Martin P. Diclofenac-induced stimulation of SMCT1 (SLC5A8) in a heterologous expression system: a RPE specific phenomenon. Biochem Biophys Res Commun. 2010 Mar 26;394(1):75-80.

Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V. Focus on the Butyrate Receptor GPR109A and the Butyrate Transporter SLC5A8. J Gastrointest Surg. 2010 Mar;14(3):449-61.

Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V. Colonic Gene Expression in Conventional and Germ-Free Mice with a Focus on the Butyrate Receptor GPR109A and the Butyrate Transporter SLC5A8. J Gastrointest Surg. 2010 Mar;14(3):449-61.

Periyasamy-Thandavan S, Jackson WH, Samaddar JS, Erickson B, Barrett JR, Raney L, Gopal E, Ganapathy V, Hill WD, Bhalla KN, Schoenlein PV. Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER(+) breast cancer cells. Autophagy. 2010 Jan 12;6(1).

Chothe P, Thakkar SV, Gnana-Prakasam JP, Ananth S, Hinton DR, Kannan R, Smith SB, Martin PM, Ganapathy V. Identification of a Novel Sodium-coupled Oligopeptide Transporter (SOPT2) in Mouse and Human Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):413-20.

Anderson CM, Jevons M, Thangaraju M, Edwards N, Conlon NJ, Woods S, Ganapathy V, Thwaites DT. Transport of the
photodynamic therapy agent 5-aminolevulinic acid by distinct H+-coupled nutrient carriers coexpressed in the small intestine. J Pharmacol Exp Ther. 2010 Jan;332(1):220-8.

Gnana-Prakasam JP, Thangaraju M, Liu K, Ha Y, Martin PM, Smith SB, Ganapathy V. Absence of iron-regulatory protein Hfe results in hyperproliferation of retinal pigment epithelium: role of cystine/glutamate exchanger. Biochem J. 2009 Nov 11;424(2):243-52.

Thangaraju M, Karunakaran SK, Itagaki S, Gopal E, Elangovan S, Prasad PD, Ganapathy V. Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate. Cancer. 2009 Oct 15;115(20):4655-66.

Tachikawa M, Kasai Y, Yokoyama R, Fujinawa J, Ganapathy V, Terasaki T, Hosoya K. The blood-brain barrier transport and cerebral distribution of guanidinoacetate in rats: involvement of creatine and taurine transporters. J Neurochem. 2009 Oct;111(2):499-509.

Gnana-Prakasam JP, Zhang M, Martin PM, Atherton SS, Smith SB, Ganapathy V. Expression of the iron-regulatory protein haemojuvelin in retina and its regulation during cytomegalovirus infection. Biochem J. 2009 May 1;419(3):533-43.
Ananth S, Karunakaran S, Martin PM, Nagineni CN, Hooks JJ, Smith SB, Prasad PD, Ganapathy V. Functional Identification of a Novel Transport System for Endogenous and Synthetic Opioid Peptides in the Rabbit Conjunctival Epithelial Cell Line CJVE. Pharm Res. 2009 May;26(5):1226-35.

Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD, Ganapathy V. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 2009 Apr 1;69(7):2826-32.

Mysona B, Dun Y, Duplantier J, Ganapathy V, Smith SB. Effects of hyperglycemia and oxidative stress on the glutamate transporters GLAST and system xc- in mouse retinal Müller glial cells. Cell Tissue Res. 2009 Mar;335(3):477-88.
Mycielska ME, Patel A, Rizaner N, Mazurek MP, Keun H, Patel A, Ganapathy V, Djamgoz MB. Citrate transport and metabolism in mammalian cells: prostate epithelial cells and prostate cancer. Bioessays. 2009 Jan;31(1):10-20. Review.

Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009 Jan;121(1):29-40.

Ganapathy V. A traffic signal for heterodimeric amino acid transporters to transfer from the ER to the Golgi. Biochem J. 2009 Jan 15;417(2):e9-11.

Thangaraju M, Carswell KN, Prasad PD, Ganapathy V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J. 2009 Jan 1;417(1):379-89.

Martin PM, Ananth S, Cresci G, Roon P, Smith S, Ganapathy V. Expression and localization of GPR109A (PUMA-G/HM74A) mRNA and protein in mammalian retinal pigment epithelium. Mol Vis. 2009;15:362-72.

Thakkar SV, Miyauchi S, Prasad PD and Ganapathy V. Stimulation of Na+/Cl-coupled opioid peptide transport system in SK-N-SH cells by L-kyotorphin, an endogenous substrate for H+-coupled peptide transporter PEPT2. Drug Metab Pharmacokinet. 2008;23(4):254-62.

Umapathy NS, Dun Y, Martin PM, Duplantier JN, Roon P, Prasad PD, Smith SB, Ganapathy V. Expression and Function of System N Glutamine Transporters (SN1/SN2 or SNAT3/SNAT5) in Retinal Ganglion Cells. Invest Ophthalmol Vis Sci. 2008 Nov;49(11):5151-60.

Thangaraju M, Cresci G, Itagaki S, Mellinger J, Browning DD, Berger FG, Prasad PD, Ganapathy V. Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2.

Anderson CM, Ganapathy V, Thwaites DT. Human solute carrier SLC6A14 is the beta-alanine carrier. J Physiol. 2008 Sep 1;586(Pt 17):4061-7.

Karunakaran S, Umapathy NS, Thangaraju M, Hatanaka T, Itagaki S, Munn DH, Prasad PD, Ganapathy V. Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy. Biochem J. 2008 Sep 15;414(3):343-55.

Smith SB, Duplantier J, Dun Y, Mysona B, Roon P, Martin PM, Ganapathy V. In vivo protection against retinal neurodegeneration by sigma receptor 1 ligand (+)-pentazocine. Invest Ophthalmol Vis Sci. 2008 Sep;49(9):4154-61.

Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10(1):193-9.

Kozlowski DJ, Chen Z, Zhuang L, Fei YJ, Navarre S, Ganapathy V. Molecular characterization and expression pattern of taurine transporter in zebrafish during embryogenesis. Life Sci. 2008 May 7;82(19-20):1004-11.

Talukder JR, Kekuda R, Saha P, Prasad PD, Ganapathy V, Sundaram U. Functional characterization, localization, and molecular identification of rabbit intestinal N-amino acid transporter. Am J Physiol Gastrointest Liver Physiol. 2008 Jun;294(6):G1301-10.

Kashiwagi H, Yamazaki K, Takekuma Y, Ganapathy V, Sugawara M. Regulatory mechanisms of SNAT2, an amino acid transporter, in L6 rat skeletal muscle cells by insulin, osmotic shock and amino acid deprivation. Amino Acids. 2009 Feb;36(2):219-30.

Kwon IK, Schoenlein PV, Delk J, Liu K, Thangaraju M, Dulin NO, Ganapathy V, Berger FG, Browning DD. Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis. Cancer. 2008 Apr 1;112(7):1462-70.

Metzner L, Natho K, Zebisch K, Dorn M, Bosse-Doenecke E, Ganapathy V, Brandsch M. Mutational analysis of histidine residues in the human proton-coupled amino acid transporter PAT1. Biochim Biophys Acta. 2008 Apr;1778(4):1042-50.

Gnana-Prakasam JP, Martin PM, Mysona BA, Roon P, Smith SB, Ganapathy V. Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe.Biochem J. 2008 Apr 1;411(1):79-88.

Dun Y, Duplantier J, Roon P, Martin PM, Ganapathy V, Smith SB. Serine racemase expression and D-serine content are developmentally regulated in neuronal ganglion cells of the retina. J Neurochem. 2008 Feb;104(4):970-8.

Umapathy NS, Gnana-Prakasam JP, Martin PM, Mysona B, Dun Y, Smith SB, Ganapathy V, Prasad PD. Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types. Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5299-305.

Dun Y, Thangaraju M, Prasad P, Ganapathy V, Smith SB. Prevention of excitotoxicity in primary retinal ganglion cells by (+)-pentazocine, a sigma receptor-1 specific ligand. Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4785-94.

Shekhawat PS, Srinivas SR, Matern D, Bennett MJ, Boriack R, George V, Xu H, Prasad PD, Roon P, Ganapathy V. Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2(-/-)) mice. Mol Genet Metab. 2007 Dec;92(4):315-24.

Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K. IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression. J Immunol. 2007 Oct 1;179(7):4775-82.

Srinivas SR, Prasad PD, Umapathy NS, Ganapathy V, Shekhawat PS. Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). Am J Physiol Gastrointest Liver Physiol. 2007 Nov;293(5):G1046-53.

Deuther-Conrad W, Patt JT, Lockman PR, Allen DD, Patt M, Schildan A, Ganapathy V, Steinbach J, Sabri O, Brust P. Norchloro-fluoro-homoepibatidine (NCFHEB) – a promising radioligand for neuroimaging nicotinic acetylcholine receptors with PET. Eur Neuropsychopharmacol. 2008 Mar;18(3):222-9.

Publications are updated quarterly. For a complete listing, see Dr. Ganapathy’s work on PubMed.

Books and book chapters

  • Ganapathy V and Fujita T. (2006) Identity of the high-affinity sodium/carboxylate cotransporter NaC3 as the N-acetyl-L-aspartate transporter. In: N-Acetylaspartate. A Unique Neuronal Molecule in the Central Nervous System. Advances in Experimental Medicine and Biology (eds. Moffett JR, Tieman SB, Weinberger DR, Coyle JT and Namboodiri AMA), Vol. 576, pp. 67-76. Springer, New York.
  • Ganapathy V, Ganapathy ME and Inoue K. (2007) Cloning of sigma-1 receptor and structural analysis of its gene and promoter region. In: Sigma Receptors: Chemistry, Cell Biology, and Clinical Implications (eds. Matsumoto RR, Bowen WD and Su TP), pp. 99-112. Springer, New York.
  • Ganapathy V, Ananth S, Smith SB and Martin PM. (2007) Vitamin C transporters in the retina. In: Ocular Transporters in Diseases and Drug Delivery (eds. Tombran-Tink J and Barnstable CJ), pp. 421-434. The Human Press, Totowa, New Jersey.
  • Ganapathy V, Ganapathy ME and Leibach FH. (2008) Protein digestion and assimilation. In: Textbook of Gastroenterology (eds. Yamada T, Alpers DH, Kalloo, AN, Kaplowitz N, Owyang C and Powell DW) 5th edition, pp. 464-477. Blackwell Publishing.

 

 Affiliations

  • Professor, Obstetrics and Gynecology, Physiology, Surgery, Biochemistry and Molecular Biology, College of Graduate Studies, Georgia Health Sciences University
  • Member, American Society of Biochemistry and Molecular Biology
  • Member, American Physiological Society
  • Member, Association of Medical and Graduate Departments of Biochemistry
  • Member, Association for Research in Vision and Ophthalmology
  • Member, International Federation of Placenta Associations