Siva Kumar Kolluri

 sivakolluri

Associate Professor of Cancer Research
Dept: EMT (1145 Ag. Life Sciences)
Phone: 541-737-1799
Fax: 541-737-0497
Siva.Kolluri@oregonstate.edu

Our research efforts are directed toward discovering molecular targets that are selective for cancer, developing agents that are selectively toxic to cancer cells, and devising optimal combinations of therapeutic agents aimed at different molecular pathways for the prevention and treatment of cancer. We are currently focusing our efforts in understanding the role of PER-ARNT-SIM (PAS) homology-domain proteins in carcinogenesis and developing small molecules to treat Bcl-2 overexpressing cancers.

Nuclear Receptors as Therapeutic Targets in Cancer: Nuclear receptors are a large superfamily of ligand-modulated transcription factors comprising receptors for steroids, retinoids and thyroid hormones. Nuclear receptors regulate a wide variety of processes and play a key role in development, physiology and disease. The estrogen receptor, retinoic acid receptor, vitamin D receptor, androgen receptor and peroxisome proliferators-activated receptor are examples of ligand-activated transcription factors. Nuclear receptors have ligand binding pockets, which can be targeted by small molecules to modulate their function and therefore are suitable pharmacological targets. Many of these receptors potently regulate cell growth and differentiation. Because of this they are excellent molecular targets for developing anti-cancer therapeutics. Our research goal is to understand the mechanism of action of some of these receptors in both normal and cancer cells and to develop nuclear receptor-based therapeutics for prevention and treatment of cancer.

Understanding Ah Receptor Signaling: Dioxins are ubiquitous environmental pollutants and are potent mammalian toxins. Ah receptor (AhR), a ligand activated transcription factor belonging to the basic-helix-loop-helix (bHLH)-Per-AhR/Arnt-Sim (PAS) protein family, mediates the toxicity of dioxins and structural analogues. We are investigating AhR-mediated actions in cancer, in the immune system (in collaboration with Dr. Nancy Kerkvliet) and in zebrafish models (in collaboration with Dr. Robert Tanguay).

Hypoxia-inducible Factor as a Target for Cancer Therapy: A major strategy in developing new cancer chemotherapeutics is to identify and target biological processes that differ between normal and malignant cells. Hypoxia, a reduction in the normal level of oxygen in tissue, occurs during cancer progression. Tumors become hypoxic because their new blood vessels are abnormal and they outgrow their blood supply. Cancer cells undergo genetic and adaptive changes that allow them to survive and proliferate in a hypoxic environment. These processes contribute to malignancy and aggressive tumor behavior.

Hypoxia inducible factor 1 (Hif-1) is a key protein factor induced by hypoxia and is involved in determining the levels of many protein factors in cancer cells. Vascular endothelial growth factor (VEGF), which promotes new blood vessel growth in tumors, is one of the important genes induced by Hif-1. Other genes regulated by Hif-1 activation are expressed at higher levels in cancer cells than in their normal tissue counterparts, and have roles in progression cancer. Hif-1 activity is also correlated with poor response to radiation therapy and chemotherapy. Our laboratory is interested in identifying pathways that disrupt Hif-1signaling in cancer cells in order to develop novel cancer therapeutics.

 

ACADEMIC QUALIFICATIONS AND POSITIONS

 

Assistant Professor (Cancer Biology)
Oregon State University, Corvallis, OR

2006-2012

Research Assistant Professor
Burnham Institute for Medical Research, La Jolla, CA

2005-2006

Staff Scientist
Burnham Institute for Medical Research, La Jolla, CA

2002-2004

Post Doctoral Work
with Dr. Xiao-Kun Zhang, Burnham Institute for Medical Research, La Jolla, CA

1999-2002

Ph.D.
The Institute of Genetics, University of Karlsruhe, Germany
(Director: Professor Peter Herrlich)
Advisor: Dr. Martin Göttlicher

1995-1999

Master of Technology (Bio Technolgy)
Jadavpur University, Calcutta, India

 

Bachelor of Pharmacy (Hons.)
Biria Institute of Technology and Science, Pilani, India

 


 

HONORS

  • Awarded University gold medal for being a topper at Jadavpur University, Calcutta, India (1990).

  • Awarded Ph.D. degree with magna cum laude (1999).

  • Short-listed for the prestigious Era of Hope Scholar award from the Breast Cancer Research Program, Department of Defense (2004).

RESEARCH GRANTS/SCHOLARSHIPS

  • New Investigator Award from California Tobacco Related Disease Research Program (2003-2006).

  • Post-doctoral fellowship from Department of Defense Breast Cancer Research Program (2000-2003).

  • Fellowship for doctoral work from Research Center Karlsruhe, Germany (1995-98).

PATENTS

  • Göttlicher, M., Kolluri, S.K., and Weiss, C. Method for evaluation of toxicity of environmental pollutants. Patent No. # Europe 198 11 326, 1999.

  • Göttlicher, M., Kolluri, S.K., and Weiss, C. Method for producing agents for treating tumor diseases and for immunosuppression Patent No. # US 6,482,610 B1, 2002.

  • Reed, J.C., Zhang, X., Gao, B., Lin, B. and Kolluri, S.K. Bcl-2 Converters for Cancer. US Patent No. # 6,994,979, 2006.

EXPERIENCE IN BIOTECH INDUSTRY (1990-1995) As Officer (Technology Transfer Operations) with Pasteur Merieux Connaught (currently Aventis Pharma), Lyon, France. Worked in the areas of quality assurance, pharmaceutical production, validation of processes, training of personnel and production planning and inventory control. Part of the team responsible for the clinical trails of injectable polio vaccine.

 


Coverage of our recent research publications:

 

Osteoporosis drug may treat breast and liver cancers (O’Donnell et al., 2014).

 

NIEHS-funded researchers discover novel compound that could treat autoimmune diseases (Punj et al., 2014).

 

PUBLICATIONS

O'Donnell EF, Koch DC, Bisson WH, Jang HS, Kolluri SK. The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells. Cell Death Dis. 2014;5:e1038. doi: 10.1038/cddis.2013.549. PMID: 24481452   

Punj S, Kopparapu P, Jang HS, Phillips JL, Pennington J, Rohlman D, O'Donnell  E, Iversen PL, Kolluri S.K, Kerkvliet NI. Benzimidazoisoquinolines: A New Class of Rapidly Metabolized Aryl Hydrocarbon Receptor (AhR) Ligands that Induce AhR-Dependent Tregs and Prevent Murine Graft-Versus-Host Disease. PLoS One. 2014;9(2):e88726. PMID: 24586378

O'Donnell EF, Kopparapu PR, Koch DC, Jang HS, Phillips JL, Tanguay RL, Kerkvliet NI, Kolluri SK. The aryl hydrocarbon receptor mediates Leflunomide-induced growth inhibition of melanoma cellsPLoS One 2012;7(7):e40926. PMID: 22815870

Sengupta S, Bisson WH, Mathew LK, Kolluri SK, Tanguay RL. Alternate glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model. Comp Biochem Physiol CToxicol Pharmacol. 156(2):121-9, 2012.

Benninghoff AD, Bisson WH, Koch DC, Ehresman DJ, Kolluri SK, Williams DE. Estrogen-like activity of perfluoroalkyl acids in vivo and interaction with human and rainbow trout estrogen receptors in vitro. Toxicol Sci. 120:42-58, 2011.

Smith KJ, Murray IA, Tanos R, Tellew J, Boitano AE, Bisson WH, Kolluri SK, Cooke MP, Perdew GH. Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J Pharmacol Exp Ther. 338:318-27, 2011.

Murray IA, Flaveny CA, Chiaro CR, Sharma AK, Tanos RS, Schroeder JC, Amin SG,  Bisson WH, Kolluri SK, Perdew GH. Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3', 4'-dimethoxy-{alpha}-naphthoflavone. Mol Pharmacol. 79:508-19, 2011.

Zhou H, Liu W, Su Y, Wei Z, Liu J, Kolluri SK, et al., NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell. 17: 560-73, 2010.

O'Donnell EF, Saili KS, Koch DC, Kopparapu PR, Farrer D, Bisson WH, Mathew LK, Sengupta S, Kerkvliet NI, Tanguay RL, Kolluri SK. The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS One. 2010 Oct 1;5(10). pii: e13128.

Bisson, W., Koch, D., O’Donnell, E., Kerkvliet, N., Tanguay, R., Abagyan, R., and Kolluri SK. Modeling of the AhR ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands. Journal of Medicinal Chemistry, 52:5635-41, 2009.

Kolluri SK, Zhu X, Zhou X, Lin B, Chen Y, Sun K, Tian X, Town J, Cao X, Lin F, Zhai D, Kitada S, Luciano F, O'Donnell E, Cao Y, He F, Lin J, Reed JC, Satterthwait AC, Zhang XK. A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell. 2008 Oct 7;14(4):285-98.

News and views of the above Cancer Cell article

Bing Qi & J Marie Hardwick Bcl-2 turns deadly. Nature Chemical Biology, 4: 722-23, 2008.

Martz, L. BCL-2 double take; Nature Science-Business exchange; 1(39); doi:10.1038 scibx.2008.938.

Flemming, A. New strategies to tip the BCL-2 balance. Nature Reviews Drug Discovery, 7:977, 2008.

Aschheim, K., DeFrancesco, L., and Hare, P. Flipping for apoptosis. Nature Biotechnology 26:1250, 2008.

Luciano F, Krajewska M, Ortiz-Rubio P, Krajewski S, Zhai D, Faustin B, Bruey JM, Bailly-Maitre B, Lichtenstein A, Kolluri S.K., Satterthwait AC, Zhang XK, Reed JC. Nur77 converts phenotype of Bcl-B, an anti-apoptotic protein expressed in plasma cells and myeloma. Blood. 2007 Feb 13; [Epub ahead of print]

Han, Y-H., Cao, X., Lin, B., Lin, F., Kolluri, S.K., Stebbins, J., Reed, J.C., Dawson, M.I., and Zhang, X.k. Regulation of Nur77 unclear export by c-Jun N-terminal kinase and Akt. Oncogene. 25: 2974-86, 2006.

Weiss C, Faust D, Durk H, Kolluri SK, Pelzer A, Schneider S, Dietrich C, Oesch F, Gottlicher M. TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38-MAPK-dependent pathway. Oncogene. 2005 Jul 21;24(31):4975-83.

Kolluri SK, Corr M, James SY, Bernasconi M, Lu D, Liu W, Cottam HB, Leoni LM, Carson DA, Zhang XK. The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2525-30. Epub 2005 Feb 7.

Cao X, Liu W, Lin F, Li H, Kolluri SK, Lin B, Han YH, Dawson MI, Zhang XK. Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. Mol Cell Biol. 2004 Nov;24(22):9705-25. Erratum in: Mol Cell Biol. 2005 Jan;25(1):524.

Cavasotto CN, Liu G, James SY, Hobbs PD, Peterson VJ, Bhattacharya AA, Kolluri SK, Zhang XK, Leid M, Abagyan R, Liddington RC, Dawson MI. Determinants of retinoid X receptor transcriptional antagonism. J Med Chem. 2004 Aug 26;47(18):4360-72.

Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 2004 Feb 20;116(4):527-40.

Kolluri SK, Bruey-Sedano N, Cao X, Lin B, Lin F, Han YH, Dawson MI, Zhang XK. Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol. 2003 Dec;23(23):8651-67.

James SY, Lin F, Kolluri SK, Dawson MI, Zhang XK. Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells. Cancer Res. 2003 Jul 1;63(13):3531-8.

Lin F, Kolluri SK, Chen GQ, Zhang XK. Regulation of retinoic acid-induced inhibition of AP-1 activity by orphan receptor chicken ovalbumin upstream promoter-transcription factor. J Biol Chem. 2002 Jun 14;277(24):21414-22. Epub 2002 Apr 4.

Kolluri SK, Balduf C, Hofmann M, Gottlicher M. Novel target genes of the Ah (dioxin) receptor: transcriptional induction of N-myristoyltransferase 2. Cancer Res. 2001 Dec 1;61(23):8534-9.

Dawson MI, Hobbs PD, Peterson VJ, Leid M, Lange CW, Feng KC, Chen Gq, Gu J, Li H, Kolluri SK, Zhang Xk, Zhang Y, Fontana JA. Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. Cancer Res. 2001 Jun 15;61(12):4723-30.

Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD, Lin B, Chen G, Lu J, Lin F, Xie Z, Fontana JA, Reed JC, Zhang X. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 2000 Aug 18;289(5482):1159-64.

Lin F, Xiao D, Kolluri SK, Zhang X. Unique anti-activator protein-1 activity of retinoic acid receptor beta. Cancer Res. 2000 Jun 15;60(12):3271-80.

Lin B, Chen GQ, Xiao D, Kolluri SK, Cao X, Su H, Zhang XK. Orphan receptor COUP-TF is required for induction of retinoic acid receptor beta, growth inhibition, and apoptosis by retinoic acid in cancer cells. Mol Cell Biol. 2000 Feb;20(3):957-70.

Kolluri SK, Weiss C, Koff A, Gottlicher M. p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes Dev. 1999 Jul 1;13(13):1742-53.

Gupta SK, Chadha K, Harris JD, Yurewicz EC, Sacco AG, Kolluri SK, Afzalpurka A. Mapping of epitopes on porcine zona pellucida-3 alpha by monoclonal antibodies inhibiting oocyte-sperm interaction. Biol Reprod. 1996 Aug;55(2):410-5.

Weiss C, Kolluri SK, Kiefer F, Gottlicher M. Complementation of Ah receptor deficiency in hepatoma cells: negative feedback regulation and cell cycle control by the Ah receptor. Exp Cell Res. 1996 Jul 10;226(1):154-63.

Kolluri SK, Kaul R, Banerjee K, Gupta SK. Nucleotide sequence of cDNA encoding bonnet monkey (Macaca radiata) zona pellucida glycoprotein-ZP3. Reprod Fertil Dev. 1995;7(5):1209-12.