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.
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 (in collaboration with Dr. Ruben Abagyan, University of California-San Diego and Dr. William Bisson at OSU) 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), in zebrafish (in collaboration with Dr. Robert Tanguay) and we are examining the required properties of selective AhR modulators in regulating AhR mediated actions (in collaboration with Dr. Gary Perdew, Penn State University).
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 (research conducted with Drs. Xiao-kun Zhang, Arnold Satterthwait and John Reed). 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.
A major goal of our laboratory is identify small molecules that convert Bcl-2 from a protector to a killer protein and establish their therapeutic efficacy in various cancer models.
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.
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. 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 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 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
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.
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.
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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.