Activator protein-1 (AP1) is a transcription factor that consists of the Jun and Fos family proteins. It regulates gene expression in response to a variety of stimuli and controls cellular processes including proliferation, transformation, inflammation, and innate immune responses. AP1 binds specifically to 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element 5′-TGAG/CTCA-3′ (AP1 site). It has been found constitutively active in breast, ovarian, cervical, and lung cancers. Numerous studies have shown that inhibition of AP1 could be a promising strategy for cancer therapeutic applications. The present in silico study provides insights into the inhibition of Jun-Fos-DNA complex formation by curcumin derivatives. These derivatives interact with the amino acid residues like Arg155 and Arg158 which play a key role in binding of Jun-Fos complex to DNA (AP1 site). Ala151, Ala275, Leu283, and Ile286 were the residues present at binding site which could contribute to hydrophobic contacts with inhibitor molecules. Curcumin sulphate was predicted to be the most potent inhibitor amongst all the natural curcumin derivatives docked. 1. Introduction Activator protein-1 (AP1) is a transcription factor that consists of either homo- or heterodimers of the Jun and Fos family proteins [1]. It regulates gene expression in response to a variety of stimuli, including environmental stresses, UV radiation, cytokines, and growth factors. AP1 in turn controls a number of cellular processes including proliferation, transformation, inflammation, and innate immune response. The Jun and Fos proteins share similar amino acid sequences that comprise the basic DNA-binding sequence and the adjacent leucine zipper region by which these proteins dimerize [2–4]. The AP1 transcription factor binds specifically to 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element 5′-TGAG/CTCA-3′ which is commonly referred to as the AP1 site [5, 6]. C-fos and c-jun genes are autoregulated; the transcription of c-jun is stimulated by its own product, and in contrast c-fos is negatively autoregulated [7–9]. AP1 has been found constitutively active in many cancers including breast, ovarian, cervical, and lung. Numerous studies have shown that inhibition of AP1 has a profound effect on the behavior of cancer cells and tumors suggesting that AP1 could be a promising target for cancer therapy [10]. Curcumin, a dietary spice derived from the plant Turmeric (Curcuma longa), is used as a traditional medicine for inflammatory conditions [11]. Further, curcumin has been reported to have
References
[1]
R. Eferl and E. F. Wagner, “AP-1: a double-edged sword in tumorigenesis,” Nature Reviews Cancer, vol. 3, no. 11, pp. 859–868, 2003.
[2]
T. Curran and B. R. Franza, “Fos and jun: the AP-1 connection,” Cell, vol. 55, no. 3, pp. 395–397, 1988.
[3]
P. F. Johnson and S. L. McKnight, “Eukaryotic transcriptional regulatory proteins,” Annual Review of Biochemistry, vol. 58, pp. 799–839, 1989.
[4]
P. J. Mitchell and R. Tjian, “Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins,” Science, vol. 245, no. 4916, pp. 371–378, 1989.
[5]
W. Lee, P. Mitchell, and R. Tjian, “Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements,” Cell, vol. 49, no. 6, pp. 741–752, 1987.
[6]
P. Angel, M. Imagawa, R. Chiu et al., “Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor,” Cell, vol. 49, no. 6, pp. 729–739, 1987.
[7]
P. Angel, K. Hattori, T. Smeal, and M. Karin, “The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1,” Cell, vol. 55, no. 5, pp. 875–885, 1988.
[8]
P. Angel and M. Karin, “The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation,” Biochimica et Biophysica Acta, vol. 1072, no. 2-3, pp. 129–157, 1991.
[9]
P. Sassone-Corsi and I. M. Verma, “Modulation of c-fos gene transcription by negative and positive cellular factors,” Nature, vol. 326, no. 6112, pp. 507–510, 1987.
[10]
E. Shaulian and M. Karin, “AP-1 as a regulator of cell life and death,” Nature Cell Biology, vol. 4, no. 5, pp. E131–E136, 2002.
[11]
H. P. T. Ammon and M. A. Wahl, “Pharmacology of Curcuma longa,” Planta Medica, vol. 57, no. 1, pp. 1–7, 1991.
[12]
R. C. Srimal and B. N. Dhawan, “Pharmacology of diferuloyl methane (curcumin), a non steroidal anti inflammatory agent,” Journal of Pharmacy and Pharmacology, vol. 25, no. 6, pp. 447–452, 1973.
[13]
O. P. Sharma, “Antioxidant activity of curcumin and related compounds,” Biochemical Pharmacology, vol. 25, no. 15, pp. 1811–1812, 1976.
[14]
S. Toda, T. Miyase, and H. Arichi, “Natural antioxidants. III. Antioxidative components isolated from rhizome of Curcuma longa L,” Chemical and Pharmaceutical Bulletin, vol. 33, no. 4, pp. 1725–1728, 1985.
[15]
R. R. Satoskar, S. J. Shah, and S. G. Shenoy, “Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation,” International Journal of Clinical Pharmacology Therapy and Toxicology, vol. 24, no. 12, pp. 651–654, 1986.
[16]
A. H. Conney, T. Lysz, T. Ferraro et al., “Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin,” Advances in Enzyme Regulation, vol. 31, pp. 385–396, 1991.
[17]
M. T. Huang, E. E. Deschner, H. L. Newmark, Z. Y. Wang, T. A. Ferraro, and A. H. Conney, “Effect of dietary curcumin and ascorbyl palmitate on azoxymethanol-induced colonic epithelial cell proliferation and focal areas of dysplasia,” Cancer Letters, vol. 64, no. 2, pp. 117–121, 1992.
[18]
M. T. Huang, Y. R. Lou, W. Ma, H. L. Newmark, K. R. Reuhl, and A. H. Conney, “Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice,” Cancer Research, vol. 54, no. 22, pp. 5841–5847, 1994.
[19]
C. V. Rao, A. Rivenson, B. Simi, and B. S. Reddy, “Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound,” Cancer Research, vol. 55, no. 2, pp. 259–266, 1995.
[20]
R. Mohan, J. Sivak, P. Ashton et al., “Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B,” Journal of Biological Chemistry, vol. 275, no. 14, pp. 10405–10412, 2000.
[21]
T. S. Huang, S. C. Lee, and J. K. Lin, “Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 12, pp. 5292–5296, 1991.
[22]
S. S. Han, Y. S. Keum, H. J. Seo, and Y. J. Surh, “Curcumin suppresses activation of NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells,” Journal of Biochemistry and Molecular Biology, vol. 35, no. 3, pp. 337–342, 2002.
[23]
M. Hergenhahn, U. Soto, A. Weninger et al., “The chemopreventive compound curcumin is an efficient inhibitor of Epstein-Barr virus BZLF1 transcription in Raji DR-LUC cells,” Molecular Carcinogenesis, vol. 33, no. 3, pp. 137–145, 2002.
[24]
A. Mukhopadhyay, C. Bueso-Ramos, D. Chatterjee, P. Pantazis, and B. B. Aggarwal, “Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines,” Oncogene, vol. 20, no. 52, pp. 7597–7609, 2001.
[25]
K. Nakamura, Y. Yasunaga, T. Segawa et al., “Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines,” International Journal of Oncology, vol. 21, no. 4, pp. 825–830, 2002.
[26]
G. Kang, P. J. Kong, Y. J. Yuh et al., “Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells,” Journal of Pharmacological Sciences, vol. 94, no. 3, pp. 325–328, 2004.
[27]
S. Park, D. K. Lee, and C. H. Yang, “Inhibition of fos-jun-DNA complex formation by dihydroguaiaretic acid and in vitro cytotoxic effects on cancer cells,” Cancer Letters, vol. 127, no. 1-2, pp. 23–28, 1998.
[28]
E. R. Hahm, G. Cheon, J. Lee, B. Kim, C. Park, and C. H. Yang, “New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex,” Cancer Letters, vol. 184, no. 1, pp. 89–96, 2002.
[29]
C. H. Park, J. H. Lee, and C. H. Yang, “Curcumin derivatives inhibit the formation of Jun-Fos-DNA complex independently of their conserved cysteine residues,” Journal of Biochemistry and Molecular Biology, vol. 38, no. 4, pp. 474–480, 2005.
[30]
H. K. Kim and C. H. Yang, “Synthetic curcumin derivatives inhibit Jun-Fos-DNA complex formation,” Bulletin of the Korean Chemical Society, vol. 25, no. 12, pp. 1769–1774, 2004.
[31]
J. L. Yap, J. Chauhan, K.-Y. Jung, L. Chen, E. V. Prochownik, and S. Fletcher, “Small-molecule inhibitors of dimeric transcription factors: antagonism of protein-protein and protein-DNA interactions,” Medicinal Chemistry Communications, vol. 3, no. 5, pp. 541–551, 2012.
[32]
M. F. Sanner, “Python: a programming language for software integration and development,” Journal of Molecular Graphics and Modelling, vol. 17, no. 1, pp. 57–61, 1999.
[33]
G. M. Morris, D. S. Goodsell, R. S. Halliday et al., “Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function,” Journal of Computational Chemistry, vol. 19, no. 14, pp. 1639–1662, 1998.
