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Our current studies focus on the regulation of prostate cancer growth and identification of novel approaches for therapeutic targeting of prostate cancer, especially castration-resistant prostate cancer (CRPC). Areas of emphasis are: 1) The role of the androgen-induced androgen receptor signaling in prostate cancer; 2) Regulation of prostate cancer by androgen receptor-independent pathways.
1. Androgen Receptor and Prostate Cancer.
The androgen receptor (AR) is a ligand-regulated transcription factor and a member of the family of nuclear receptors that are activated in response to the signaling from lipophilic, small-molecule hormones and metabolites. We provided the first evidence for a negative role of the nuclear factor-kappaB (NF-κB), and positive role of a multi-protein complex that includes B-MYB (a proto-oncoprotein), PARP-1 (poly ADP-ribose polymerase) and hnRNPK (a RNA-binding/pre-mRNA processing ribonucleoprotein). Beyond molecular studies, the impact of this multi-protein complex on AR activity in prostate cancer is being investigated. Major current emphasis has been to follow up on our two novel findings concerning i) methylation of AR and enhanced activity of methylated AR; ii) loss of a steroid- and cholesterol-sulfating sulfotransferase (SULT2B) in prostate cancer.
We have reported that AR is lysine-methylated by SET9 methyltransferase, and methylation endows AR with enhanced activity. Reactivated AR in a castrate-level androgen environment, leading to CRPC, may arise in part due to elevated levels/activity of methyl-modified AR in tumors. Polyclonal antibodies specific to methylated AR are being validated for immunohistochemistry (IHC). A second project is to examine functional interactions between the AR pathway and the vitamin D receptor (VDR) signaling axis in the regulation of prostate cancer cell growth. Vitamin D is known to confer growth inhibition to prostate cancer cells. We have recently reported that prostate cancer is associated with statistically significant marked loss in the expression of the sulfotransferase SULT2B. Since SULT2B acts preferentially on cholesterol and DHEA (precursor steroid for dihydrotestosterone), we hypothesize that loss of SULT may promote de novo androgen synthesis in prostate by increasing free DHEA pool. This in turn can activate AR signaling and promote CRPC. Intriguingly, SULT2B is induced by VDR. The prognostic and therapeutic significance of reduced SULT2B expression in prostate cancer is being explored.
2. Natural Products in the regulation of prostate cancer growth.
Natural products such as salinomycin, which is an antibiotic product of the bacterium Streptomyces albus and deoxypodophyllotoxin (DPT), which is a Himalayan medicinal plant lignin, have strong anti-prostate cancer activity. Furthermore, in a collaborative project, we have demonstrated potent anti-cancer activity of an RNA virus (respiratory syncytial virus). Several intracellular signaling pathways are involved in the anti-tumor activities of these agents. Our current studies aim to establish the roles of the PI3K-AKT and Ca2+-regulated signaling axis in the reduction of prostate tumor burden by these agents in various mouse models of prostate cancer. Mechanistic details involving these pathways are expected to identify targetable molecules, which harbor the potential for providing therapeutic benefits.
We employ diverse experimental approaches related to cell and molecular biology, biochemistry, bioinformatics, antibody development and immunohistochemistry, and employ xenograft tumor models, genetically modified mouse models and clinical specimens of prostate cancer for our study.
- Kim KY, Cho HJ, Yu SN, Kim SH, Yu HS, Park YM, Mirkheshti N, Kim SY, Song CS, Chatterjee B, and Ahn SC: (2013) Interplay of reactive oxygen species, intracellular Ca(2+) and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin. [Epub ahead of print Nov 28, 2012.]J Cell Biochem. 114(5): 1124-34.
- Seo YK, Mirkheshti N, Song CS, Kim S, Dodds S, Ahn SC, Christy B, Mendez-Meza R, Ittmann MM, Abboud-Werner S, and Chatterjee B: (2013) SULT2B1b sulfotransferase: induction by vitamin D receptor and reduced expression in prostate cancer. Mol Endocrinol. doi:10.1210/me.2012-1369 [Epub ahead of print April 11, 2013.]
- Kim KY, Yu SN, Lee SY, Chun SS, Choi YL, Park YM, Song CS, Chatterjee B, and Ahn SC: (2011) Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem Biophys Res Commun. 413(1): 80-6.
- Echchgadda I, Chang TH, Sabbah A, Bakri I, Ikeno Y, Hubbard GB, Chatterjee B, and Bose S: (2011) Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense. BMC Cancer. 11: 43.
- Ko S, Ahn J, Song CS, Kim S, Knapczyk-Stwora K, and Chatterjee B: (2011) Lysine methylation and functional modulation of androgen receptor by Set9 methyltransferase. Mol Endocrinol. 25(3): 433-44.
- Alimirah F, Vaishnav A, McCormick M, Echchgadda I, Chatterjee B, Mehta RG, and Peng X: (2010) Functionality of unliganded VDR in breast cancer cells: repressive action on CYP24 basal transcription. Mol Cell Biochem. 342(1-2): 143-50.
- Echchgadda I, Kota S, Dela Cruz I, Sabbah A, Chang T, Harnack R, Mgbemena V, Chatterjee B, and Bose S: (2009) Anticancer oncolytic activity of respiratory syncitial virus. Cancer Gene Ther.16(12): 923-35.
- Shi L, Ko S, Kim S, Echchgadda I, Oh TS, Song CS, and Chatterjee B: (2008) Loss of androgen receptor in aging and oxidative stress through the Myb protooncoprotein-regulated reciprocal chromatin dynamics of p53 and poly(ADP-ribose) polymerase PARP-1. J Biol Chem. 283(52): 36474-85.
- KoS, Shi L, Kim SY, Song CS, and Chatterjee B: (2008) Interplay of nuclear factor-kappaB and B-myb in the negative regulation of androgen receptor expression by tumor necrosis factor alpha. Mol Endocrinol. 22(2): 273-86.
- Echchgadda I, Song CS, Oh T, Ahmed M, De La Cruz IJ, and Chatterjee B: (2007) The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase. Mol Endocrinol. 21(9): 2099-111.
- Seo YK, Chung YT, Kim S, Echchgadda I, Song CS, and Chatterjee B: (2007) Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: the role of a gene enhancer in the liver chromatin. Gene. 386(1-2): 218-23.
- Song CS, Echchgadda I, Seo YK, Oh T, Kim S, Kim SA, Cho S, Shi L, and Chatterjee B: (2006) An essential role of the CAAT/enhancer binding protein-alpha in the vitamin D-induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1). Mol Endocrinol. 20(4): 795-808.
- Chatterjee B, Echchgadda I, and Song CS: (2005) Vitamin D receptor regulation of the steroid/bile acid sulfotransferase SULT2A1. Methods Enzymol., “Phase II: Conjugation Enzymes, Glutathione Transferases and Transport Systems." 400: 165-91.
- Echchgadda I, Song CS, Roy AK, and Chatterjee B: (2004) Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor. Mol Pharmacol. 65(3): 720-9.
- Zhang L, Charron M, Wright WW, Chatterjee B, Song CS, Roy AK, and Brown TR: (2004) Nuclear factor-kappaB activates transcription of the androgen receptor gene in Sertoli cells isolated from testes of adult rats. Endocrinology. 145(2): 781-9.
- Chatterjee B: (2003) The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer. Mol Cell Biochem. 253(1-2): 89-101.
- Rivera OJ, Song CS, Centonze VE, Lechleiter JD, Chatterjee B, and Roy AK: (2003) Role of the promyelocytic leukemia body in the dynamic interaction between the androgen receptor and steroid receptor coactivator-1 in living cells. Mol Endocrinol. 17(1): 128-40. (cover article)
- Song CS, Echchgadda I, Baek BS, Ahn SC, Oh T, Roy AK, and Chatterjee B: (2001) Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor. J Biol Chem. 276(45): 42549-56.
- Tyagi RK, Lavrovsky Y, Ahn SC, Song CS, Chatterjee B, and Roy AK: (2000) Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells. Mol Endocrinol. 14(8): 1162-74. (cover article)
- Chen S, Song CS, Lavrovsky Y, Bi B, Vellanoweth R, Chatterjee B, and Roy AK: (1998) Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. Mol Endocrinol. 12(10): 1558-66. (cover article)
- Song CS, Jung MH, Kim SC, Hassan T, Roy AK, and Chatterjee B: (1998) Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter. J Biol Chem. 273(34): 21856-66.