Yangzom D. Bhutia, D.V.M. Ph.D.
Molecular mechanisms associated with pancreatic cancer drug resistance, biomarker identification for early detection and drug target, development of novel anticancer drugs for pancreatic and prostate cancer.
Amino acid transporters and their relevance to amino acid nutrition in cancer cells.
Amino acid transporters play an obligatory role in cancer cell proliferation. Glutamine is an important amino acid for cancer cells; without this amino acid, tumor cells do not survive. Even though glutamine is considered as a non-essential amino acid, tumor cells need this amino acid so much that their endogenous synthetic capacity does not match the increased demand. Therefore, tumor cells must rely on plasma membrane transporters to import this amino acid from blood. Tumor cells, including the pancreatic cancer cells, are “addicted” to glutamine. My lab has discovered a novel amino acid transporter, SLC6A14 to be highly upregulated in pancreatic cancer. We have also identified a pharmacological blocker of this particular transporter that can cause growth arrest and apoptosis in pancreatic cancer cells both in vitro as well as in vivo in mouse xenograft models. The current focus is to develop mouse model of pancreatic ductal adenocarcinoma (PDAC) with SLC6A14-null mice with the idea that the genetic deletion of SLC6A14 will attenuate the tumor growth in the mouse model.
SLC6A14 as a drug delivery system to overcome chemoresistance in pancreatic cancer.
Gemcitabine is currently the drug of choice to treat PDAC but the patients develop chemoresistance very fast. In order to overcome the chemoresistance we have to make the drug available to the tumor cells. So, the question is can we use SLC6A14, which is highly upregulated in PDAC as a drug delivery system. Gemcitabine is not a substrate for SLC6A14 but we can achieve this goal with an innovative approach of using a transporter-mediated prodrug delivery strategy. For tumor-specific delivery of drugs, a transporter in the plasma membrane should have broad selectivity to accept structurally diverse drugs as substrates, should be coupled to metabolic energy to concentrate drugs inside tumor cells, and most importantly, should be upregulated in tumors to enable tumor-specific accumulation of the drugs. Our studies have shown that SLC6A14 has all of these attributes and is ideal for tumor-specific delivery of gemcitabine in the form of amino acid-based prodrugs. So, the current focus is to use amino acid based prodrugs of gemcitabine and its delivery into tumor cells via SLC6A14 and thereby overcome chemoresistance in PDAC.
Repurposing FDA-approved drugs to treat pancreatic and prostate cancer.
Re-purposing FDA-approved drugs to treat cancer is a very attractive strategy due to its many advantages. If the anticancer efficacy of these drugs could be demonstrated in preclinical studies, clinical trails can be started right away to evaluate its efficacy in cancer patients without the expensive pharmacokinetic/pharmacodynamic and toxicological studies. It can be highly cost-effective. With this idea the focus here is to screen FDA-approved drugs that could be used as an anticancer agent to treat pancreatic and prostate cancer.
- Ristic B. and Bhutia, Y.D. (2017) Cell-surface G-protein-coupled receptor for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer. Biochim Biophys Acta 1868; 246-257. PubMed
- Bhutia Y.D., Ogura, J., Sivaprakasam, S. and Ganapathy, V. (2017) Gut microbiome and colon cancer: Role of bacterial metabolites and their molecular targets in the host. Curr Colorectal Cancer Rep DOI 10,1007/s11888-017-0362-9. PubMed
- Bhutia, Y.D., Kopel, J.J., Lawrence, J.J., Neugebauer, V. and Ganapathy V. (2017) Plasma membrane Na+- coupled citrate transporter (SLC13A5) and neonatal epileptic encephalopathy. Molecules 22(3), 378; doi:10.3390/molecules22030378 PubMed
- Coothankandaswamy, V., Cao, S., Xu, Y., Prasad, P. D., Singh, P. K., Reynolds, C.P., Yang, S., Ogura, J., Ganapathy, V., and Bhutia, Y.D. (2016) The amino acid transporter SLC6A14 is a novel and effective drug target for treatment of pancreatic cancer. British Journal of Pharmacology 173; 3292-3306. PubMed
- Bhutia, Y.D., Babu, E. and Ganapathy, V. (2016) Re-programming tumor cell metabolism to treat cancer: no lone target for lonidamine. Biochemical Journal 473:1503-6. PubMed
- Bhutia, Y.D., Babu, E., Ramachandran, S., Yang, S., Thangaraju, M. and Ganapathy, V. (2016) SLC transporters as a novel class of tumor suppressors: identity, function and molecular mechanisms. Biochemical Journal 473:1113-24. PubMed
- Bhutia, Y.D. and Ganapathy, V. (2015) Glutamine transporters in mammalian cells and their function in physiology and cancer. Biochimica et Biophysica Acta 1863:2531-9. (Invited Review for a special issue entitled “ Mitochondrial channels”). PubMed
- Babu, E., Bhutia, Y.D., Ramachandran, S., Gnana-Prakasam, J.P., Thangaraju, M., Prasad, P.D. and Ganapathy, V. (2015) Deletion of the amino acid transporter Slc6a14 suppresses tumor growth in spontaneous 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 Brand 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. J Pharmacol Exp Ther. 353 (1): 17-26. PubMed
- Hung, S. W., Marrache, S., Cummins, S., Bhutia, Y.D., Mody, H., Hooks, S. B., Dhar, S., and Govindarajan, R. (2015) Defective hCNT1 transport contributes to gemcitabine chemoresistance in ovarian cancer subtypes: Overcoming the transport defects using a nanoparticle approach. Cancer Letters 359(2): 233-40. PubMed
- Bhutia, Y.D., Ellappan, B. and Ganapathy, V. (2014). Interferon-y induces a tryptophan-selective amino acid transporter in human colonic epithelial cells and mouse dendritic cells. Biochimica et Biophysica Acta 1848: 453-462. PubMed
- Hung, S.W., Mody, H., Marrache, S., Bhutia, Y.D., Davis, F., Cho, J.H., Zastre, J., Dhar, S., Chu, C.K., and Govindarajan, R. (2013) Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: In vitro optimization and novel nanoparticle delivery studies. PLoS One 8: e71196. PubMed
- Bhutia, Y.D., Hung, S.W., Krentz, M., Patel, D., Lovin, D., Manoharan, R., Thomson, M., and Govindarajan, R. (2013) Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: Role of LIN-28 and SET oncoprotein. PLoS One 8: e53436. PubMed
- Bhutia, Y.D., Hung, S.W., Patel, B., Lovin, D., and Govindarajan, R. (2011) CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells. Cancer Research 71: 1825-1835 PubMed
- Bhutia, Y.D., Hung, S.W., Patel, B., Lovin, D., and Govindarajan, R. (2011) Modification of chemotherapy resistance in pancreatic cancer cells. Breaking Advances Highlights from Recent Cancer Literature. Cancer Research 71: 3173-3174.
- Kang, N., Jun, A.H., Bhutia, Y.D., Kannan, N., Unadkat, J., and Govindarajan, R. (2010) Human equilibrative nucleoside transporter- 3 (hENT3) spectrum disorder mutations impair nucleoside transport, protein localization and stability. Journal of Biological Chemistry 285: 28343–28352. 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, Nova Science Publishers.