Singhal-Sharad

Sharad S. Singhal, Ph.D.

  • Research Professor, Department of Molecular Medicine

Sharad S. Singhal, Ph.D.

Research Focus :
  • Carcinogenesis and Metastases
  • Chemoprevention
  • Drug Resistance
  • Radiation Resistance
  • 2016-present, Research Professor, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
  • 2011-2016, Research Professor, Department of Diabetes, Endocrinology & Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
  • 2007-2011, Associate Professor, Molecular Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX
  • 2004-2007, Research Associate Professor, Department of Chemistry and Biochemistry University of Texas at Arlington, Arlington, TX
  • 1999-2004, Research Assistant Professor, Department of Chemistry and Biochemistry University of Texas at Arlington, Arlington, TX.
  • 1997-1999, Research Assistant Professor, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX.
  • 1992-1997, Instructor, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX.
  • 1989-1992, Postdoctoral Fellow, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX.
  • Molecular Medicine
  • Diabetes and Metabolic Diseases

Degrees

  • Agra University, Agra, India, Ph.D., Biochemistry
  • Agra University, Agra, India, M.S., Chemistry
  • Agra University, Agra, India, B.S., Zoology, Botany, Chemistry
Our laboratory is interested in the interface of cell signaling and oxidative stress metabolism and its role in carcinogenesis, stress-defense, drug-resistance, radiation-resistance and insulin-resistance.  
  • RLIP76 (Ral Binding Protein, RalBP1) is a 76 kDa multifunctional protein associated with carcinogenesis, metastases, drug and radiation resistance. In association with Sanjay Awasthi, MD, our lab has worked on mapping the critical upstream and downstream regulators of RLIP76 in multiple phases of tumor progression and therapeutic response. RLIP76 is the major mercapturic acid pathway (MAP) transporter that functions in the ATP-dependent active efflux of glutathione (GSH) conjugates (GS-E) of products of lipid peroxidation like 4-Hydroxynonenal (4HNE) and chemotherapy drugs out of cells, thereby reducing the intracellular concentrations of toxic radicals and chemo drugs. Inhibition of the transport function of RLIP76 also reduces the signaling downstream of multiple kinase cascades like EGF, IGF and WNT pathways that are dependent on clathrin-dependent endocytosis (CDE). RLIP76 knockout mice are characteristically resistant to carcinogenesis.  Inhibition of RLIP76 function and/depleting RLIP76 sensitizes multiple cancers to drug and radiation therapy.
Sharad Singhal Fig 1
  • Our lab has worked on the efficacy and mechanisms of the anticancer effects induced by 2’-hydroxyflavanone (2HF), didymin, and vicenin-2 in renal cancer, neuroblastoma and prostate cancers, respectively. These compounds have shown preliminary efficacy in targeting multiple kinases and tumor suppressors like EGF, IGF, PI3K, c-Myc, p53, and RB pathways along with promising effect on decreasing the levels of RLIP76, the MAP transporter. Current studies in breast cancer are focused on expanding the mechanistic basis and testing the efficacy at multiple critical stages of carcinogenesis, metastases and therapeutic resistance following administration of novel chemopreventive regimens.
  • We are working on COH-SR4 (a small molecule synthesized and named after Prof. Samuel Rahbar, MD, PhD, who actively guided and directed the initial stages of project) which has shown promising anticancer and antidiabetic effects in vitro and in vivo.  COH-SR4 suppresses lipogenic genes like sterol regulatory element binding protein-1c (SREBF1), acetyl-Coenzyme A carboxylase (ACOACa), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FASN), stearoyl-Coenzyme A desaturase 1 (SCD1), carnitine palmitoyltransferase 1a (CPT1a) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), as well as gluconeogenic genes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) in the liver of obese mice.
  • COH-SR4 inhibits cell cycle kinases, decreases vimentin and fibronectin, and activates AMPK pathway while inhibiting cancer progression.
 
Mechanisms of action of COH-SR in lung cancer
 
Sharad Singhal Fig 2
 
Approach
We employ a sound combination of genetic, molecular biology and proteomic investigations in association with the City of Hope core facilities to specifically characterize the impact of candidate chemopreventive agents/chemotherapy drugs on the core signaling networks of importance in insulin resistance, oncogenic transformation and metastatic progression of cancers. This advanced and multi-disciplinary approach has made possible the integration of key essential and translational scientific parameters which expand the understanding of the molecular basis for anticancer effects of novel chemopreventive and/chemotherapeutic agents.
Lokesh Nagaprashantha, M.B.B.S., Ph.D.
Staff Scientist
Department of Molecular Medicine

Jyotsana Singhal, M.S.
Staff Scientist
Department of Molecular Medicine
 
James Figarola, Ph.D.
Research Associate Professor
Department of Diabetes Complications & Metabolism Research
  • Singhal SS, Nagaprashantha L, Singhal P, Singhal S, Singhal J, Awasthi S, Horne D. (2017) RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma. Pharm Res., [Epub ahead of print].
  • Figarola JL, Singhal J, Tompkins JD, Rogers GW, Warden C, Horne D, Riggs AD, Awasthi S, Singhal SS (2015) SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells. J Biol Chem., 290: 30321–30341.
  • Nagaprashantha, L., Talamantes, T., Singhal, J., Guo, J., Vatsyayan, R., Rauniyar, N., Awasthi, S., Singhal, S.S., Prokai, L. (2013) Proteomic analysis of signaling networks regulation in renal cell carcinoma with differential hypoxia-inducible factor-2α expression.  PLoS ONE, 8: e71654.
  • Singhal S.S., Figarola, J., Singhal, J., Nagaprashantha, L., Berz, D., Rahbar, S., and Awasthi, S. (2013) Novel compound 1, 3-bis (3, 5-dichlorophenyl) urea inhibits lung cancer progression. Biochem Pharmacol., 86: 1664-1672.
  • Singhal J, Nagaprashantha L, Vatsyayan R, Ashutosh, Awasthi, S., and Singhal SS.  (2012) Didymin induces apoptosis by inhibiting N-Myc and up-regulating RKIP in neuroblastoma. Cancer Prev Res., 5: 473-483.
  • Singhal, S.S., Figarola, J., Singhal, J., Leake, K., Nagaprashantha, L., Lincoln, C., Gigiu, G., Horn, D., Jove, R., Awasthi, S. and Rahbar, S. (2012) 1,3-bis(3,5-dichlorophenyl) urea compound ‘COH-SR4’ inhibits proliferation and activates apoptosis in melanoma. Biochem Pharmacol., 84: 1419-1427.
  • Nagaprashantha L, Vartak N, Awasthi S, Awasthi S, and Singhal SS. (2012) Novel anticancer compounds for developing combinatorial therapies to target anoikis-resistant tumors.  Pharm Res., 29: 621-636.
  • Singhal J, Nagaprashantha, L.D., Vatsyayan, R., Awasthi S, and Singhal SS. (2011) RLIP76, a glutathione-conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome.  PLoS ONE, 6: e24688.
  • Nagaprashantha, D., Vatsyayan, R., Singhal, J., Fast, S., Roby, R., Awasthi, S., and Singhal, S.S.  (2011) Anticancer effects of novel flavonoid vicenin-2 as a single agent and in synergistic combination with docetaxel in prostate cancer. Biochem Pharmacol., 82: 1100-1109.
  • Singhal, S.S., Wickramarachchi, D., Yadav, S., Singhal, J., Leake, K., Vatsyayan, R., Lelsani, P., Chaudhary, P., Suzuki, S., Suzuki, S., Yang, S., Awasthi, Y.C., and Awasthi, S. (2011) Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis. Mol Cancer Therapeutics, 10: 16-28.
  • Nagaprashantha, L.D., Vatsyayan, R., Singhal, J., Lelsani, P.C., Prokai, L., Awasthi, S. and Singhal, S.S. (2011) 2'-Hydroxyflavanone inhibits proliferation, tumor vascularization and promotes normal differentiation in VHL-mutant Renal Cell Carcinoma. Carcinogenesis, 32: 568-575.
  • Singhal, S.S., Yadav, S., Drake, K., Singhal, J. and Awasthi, S. (2008) Hsf-1 and POB1 induce drug-sensitivity and apoptosis by inhibiting Ralbp1. J. Biol. Chem., 283: 19714-19729.
  • Singhal, S.S., Singhal, J., Yadav, S., Dwivedi, S., Boor, P., Awasthi, Y.C. and Awasthi, S. (2007) Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (RALBP1). Cancer Res., 67: 4382-4389.
  • Awasthi, S., Singhal, S.S., Srivastava, S.K., Zimniak, P., Bajpai, K.K., Saxena, M., Sharma, R., Ziller, S.A.III, Frenkel, E., Singh, S.V., He, N.-G., and Awasthi, Y.C. (1994) ATP-dependent transport of doxorubicin, daunomycin and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein.  J. Clin. Invest., 93: 958-965.
  • 2005-2009, 2011, Cancer Research Foundation of North Texas award
  • 2009, Institute for Cancer Research (ICR) and Joe & Jessie Crump Fund award
  • 1987-1989, Senior Research Fellowship of the Council of Scientific and Industrial Research.
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