Siva Kumar Kolluri

Associate Professor of Cancer Research
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Office: 541-737-1799
Fax: 541-737-0497

Agricultural & Life Sciences

Agricultural & Life Sciences Building 1145

2750 SW Campus Way

2750 SW Campus Way
Corvallis, OR 97331

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.

 

Conversion of Bcl-2 from a protector to a killer in cancer cells: Bcl-2-family proteins are evolutionarily conserved regulators of cell death. The Bcl-2 family primarily acts on mitochondria to regulate cell death. Overexpression of Bcl-2 contributes to cancer development and tumor progression by blocking pro-cell death Bcl-2 family members. The overexpression of Bcl-2 correlates with poor survival and correlates with resistance of cancer cells to many chemotherapeutic drugs and radiation. 

We discovered a novel pathway in which Bcl-2 is converted from a protector to a killer protein (Cell 116, 527-540, 2004; Cancer Cell, 14:285-98, 2008; Oncotarget, 9:26072-26085, 2018). The dramatic change in Bcl-2 function is brought about by orphan nuclear receptor Nur77 binding, which exposes a hidden ‘killer BH3 domain’ of Bcl-2. We reported the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals. The apoptotic effect of NuBCPs are not inhibited but rather potentiated by Bcl-2 expression. NuBCP-9 and its enantiomer bound to the Bcl-2 loop, which shares the characteristics of structurally adaptable regions with many cancer-associated and signaling proteins. This discovery enabled extremely exciting new research possibilities, providing a molecular basis for the design and development of novel cancer therapeutics.

The major goal of our laboratory is to identify small molecules that convert Bcl-2 from a protector to a killer protein and establish their therapeutic efficacy in various cancer models.

Cancer protector into killer: https://extension.oregonstate.edu/news/osu-helps-turn-cancer-protector-killer

 

Ah Receptor as a therapeutic target in cancer: Ah receptor (AhR) is a ligand activated transcription factor belonging to the basic-helix-loop-helix (bHLH)-Per-Arnt-Sim (PAS) protein family. The bHLH/PAS family proteins are heterodimeric transcription factors that sense and respond to external or physiological signals such as hypoxia and circadian rhythms.

AhR has been implicated as a tumor suppressor and continues to gain interest as a potential therapeutic target in cancer. We have reported that high AhR expression is associated with increased relapse-free survival and distant metastasis free survival in patients with hormone independent breast cancer.  The major focus of our laboratory is to (i) investigate AhR signaling in tumor suppression and (ii) characterize the mechanism of action of Select Modulators of AhR-regulated Transcription with anti-cancer effects.

We have developed AhR ligand binding pocket models to understand AhR ligand binding pocket interactions with distinct classes of chemical compounds. We have generated new mouse models to understand AhR mediated tumor suppression in the context of p53 tumor suppressor gene deletion (in collaboration with Dr. Christiane Loehr at OSU).

We are also investigating AhR mediated signaling in the immune system (in collaboration with Dr. Nancy Kerkvliet; PLoS One, 9:e88726, 2014; Journal of immunology, 196: 264-732016, 2016; Eur J Immunol., 47:1989-2001, 2017), in zebrafish (in collaboration with Dr. Robert Tanguay) and we are examining the required properties of select AhR modulators that activate the anti-cancer actions of the AhR (Cell Death Dis., 5:e1038, 2014; Oncogene, 34:6092-104, 2015; Oncotarget, 8:25211-25225, 2017; Arch Toxicol. 91:2497-2513, 2017).

Osteoporosis drug for treatment of breast and liver cancers:  https://www.niehs.nih.gov/news/newsletter/2014/4/science-osteoporosisdrug/

New chemical to prevent Type 1 diabetes:  http://oregonstate.edu/ua/ncs/archives/2016/jan/new-chemical-could-yield-therapy-prevent-type-1-diabetes

 

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.

 

Nuclear Receptors as 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.

 

Education: 

Post Doctoral Research
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Mentor: Professor Xiao-kun Zhang

Ph.D. - Magna Cum Laude
The Institute of Genetics, Forschungszentrum Karlsruhe, Germany
(Director: Professor Peter Herrlich)
Thesis Mentor: Professor Martin Göttlicher

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

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

 

Honors: 

National Merit Scholar

University Gold Medal, Jadavpur University, Calcutta, India

Department of Defense Breast Cancer Research Program Post-doctoral Scholar

New Investigator Award of the California Tobacco Related Disease Research Program

American Cancer Society Research Scholar

 

Professional Affiliations: 

Research Faculty Member, Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University, Portland

Cancer Prevention and Intervention Program, Linus Pauling Institute, Oregon State University

Department of Biomedical Sciences, Oregon State University

Department of Biochemistry & Biophysics, Oregon State University

 

Patents

Kopparapu, P; Pearce, M and Kolluri, S.K. Bcl-2 functional converters. U.S. application 2018.

Nancy I. Kerkvliet and Siva Kumar Kolluri. Compounds and Methods to suppress autoimmune response. Application No. PCT/US15/57873; 15855322.2 (European application 2017); 15/522,241 (U.S. application 2017)

Satterthwait, A., Zhang, X.K, Zhu, X., and Kolluri, S.K. Methods of regulating apoptosis. Patent No. # US20100292145A1, 2010.

Kolluri, S.K., Zhu, X., Zhang, X., and Satterthwait, A. Targeting Bcl-2 family proteins with cell-permeable peptides. US Patent No. # 20070054863, 2008.

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.

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.

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

 

Team

1. Dr. Hyo Sang Jang: Postdoctoral Associate

2. Dr. Veronica Puig-Sanvicens: Postdoctoral Scholar

3. Martin Pearce: Graduate student

4. John Gamble: Graduate student

5. Bach Nguyen: Graduate student

6. Daniel Elson: Graduate student

7. Monica Mueller: Research Assistant

8. Brenna Stevens: Undergraduate Honors thesis student

9. Stephen En-han Oh: Undergraduate research student

10. Nick Korjeff: Undergraduate BRR thesis student

11. Sakib Tasnimul Haque: Undergraduate Honors thesis student

12. Andrew Bui: Undergraduate student

 

Select Publications: Citations: 4186, h-index: 29

Pearce, M.C., Gamble, J.T., Kopparapu, P.R., O’Donnell, E.F., Mueller, M.J., Jang, H.S., Greenwood, J.A., Satterthwait, A.C., Tanguay, R.L., Zhang, X.-K. and Kolluri, S.K. Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells. Oncotarget. 9: 26072–26085, 2018. PMID: 29899843

Kolluri, S.K, Jin UH, Safe S. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol. 91(7):2497-2513, 2017. PMID: 28508231.

Jang, H.S.; Pearce, M.; O’Donnell, E.F.; Nguyen, B.D.; Truong, L.; Mueller, M.J.; Bisson, W.H.; Kerkvliet, N.I.; Tanguay, R.L.; Kolluri, S.K. Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells. Biology, 6, 41: 2017. PubMed PMID: 29194351.

Ehrlich AK, Pennington JM, Tilton S, Wang X, Marshall NB, Rohlman D, Funatake C, Punj S, O'Donnell E, Yu Z, Kolluri S.K, Kerkvliet NI. AhR activation increases  IL-2 production by alloreactive CD4(+) T cells initiating the differentiation of  mucosal-homing Tim3(+) Lag3(+) Tr1 cells. Eur J Immunol. 47:1989-2001, 2017. PMID: 28833046.

Allison K. Ehrlich, Jamie M. Pennington, Xisheng Wang, Diana Rohlman, Sumit Punj, Christiane Loehr, Matthew T. Newman, Siva K. Kolluri, and Nancy I. Kerkvliet; Activation of the Aryl Hydrocarbon Receptor Prevents Insulitis and Effector T Cell Development Independently of Foxp3+ Regulatory T Cells in Non-obese Diabetic Mice. Journal of immunology 196: 264-732016, 2016. PMID: 26573835.

New chemical to prevent Type 1 diabetes. http://oregonstate.edu/ua/ncs/archives/2016/jan/new-chemical-could-yield-therapy-prevent-type-1-diabetes

O'Donnell EF, Jang HS, Pearce M, Kerkvliet NI, Kolluri, S.K. The aryl hydrocarbon receptor is required for induction of p21cip1/waf1 expression and growth inhibition by SU5416 in hepatoma cells. Oncotarget. 8(15):25211-25225, 2017. PMID: 28424418.

Koch DC, Jang HS, O'Donnell EF, Punj S, Kopparapu PR, Bisson WH, Kerkvliet NI, Kolluri SK. Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1. Oncogene. 34:6092-104, 2015. PMID: 25867062

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 and Disease. 2014;5:e1038. doi: 10.1038/cddis.2013.549. PMID: 24481452   

Osteoporosis drug for treatment of breast and liver cancers.   https://www.niehs.nih.gov/news/newsletter/2014/4/science-osteoporosisdrug/

Punj S, Kopparapu P, Jang HS, Phillips JL, Pennington J, Rohlman D, O'Donnell  E, Iversen PL, Kolluri SK, 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

Researchers discover novel compound for treat autoimmune diseases.  https://www.niehs.nih.gov/news/newsletter/2014/5/science-autoimmune/index.htm

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 cells.  PLoS ONE. 7(7): e40926, 2012.

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. Molecular Pharmacology. 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.

Bisson, W., Koch, D., O’Donnell, E., Khalil, S., Kerkvliet, N., Tanguay, R., Abagyan, R., and Kolluri, S.K. Modeling of the Aryl Hydrocarbon Receptor(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.

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.

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.

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.

Kolluri, SK., Balduf C., Hofmann M. and Goettlicher, M. Novel target genes of the Ah (Dioxin) receptor: transcriptional induction of N-myristoyltransferase 2. Cancer Research 61: 8534-9, 2001.

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.

 

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At OSU
Affiliated with: 
Molecular and Cellular Biology
Courses Taught: 

Tox 699: Molecular Therapeutics - Discovery and Development

Headquarters: 
OSU Main Campus
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