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http://dx.doi.org/10.4196/kjpp.2013.17.4.291

Mutant p53-Notch1 Signaling Axis Is Involved in Curcumin-Induced Apoptosis of Breast Cancer Cells  

Bae, Yun-Hee (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University)
Ryu, Jong Hyo (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University)
Park, Hyun-Joo (Department of Oral Physiology, School of Dentistry, Yangsan Campus of Pusan National University)
Kim, Kwang Rok (Korea Research Institute of Chemical Technology)
Wee, Hee-Jun (College of Pharmacy, Seoul National University)
Lee, Ok-Hee (Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases, Yonsei University Health System)
Jang, Hye-Ock (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University)
Bae, Moon-Kyoung (Department of Oral Physiology, School of Dentistry, Yangsan Campus of Pusan National University)
Kim, Kyu-Won (College of Pharmacy, Seoul National University)
Bae, Soo-Kyung (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.17, no.4, 2013 , pp. 291-297 More about this Journal
Abstract
Notch1 has been reported to be highly expressed in triple-negative and other subtypes of breast cancer. Mutant p53 (R280K) is overexpressed in MDA-MB-231 triple-negative human breast cancer cells. The present study aimed to determine whether the mutant p53 can be a potent transcriptional activator of the Notch1 in MDA-MB-231 cells, and explore the role of this mutant p53-Notch1 axis in curcumin-induced apoptosis. We found that curcumin treatment resulted in an induction of apoptosis in MDA-MB-231 cells, together with downregulation of Notch1 and its downstream target, Hes1. This reduction in Notch1 expression was determined to be due to the decreased activity of endogenous mutant p53. We confirmed the suppressive effect of curcumin on Notch1 transcription by performing a Notch1 promoter-driven reporter assay and identified a putative p53-binding site in the Notch1 promoter by EMSA and chromatin immunoprecipitation analysis. Overexpression of mutant p53 increased Notch1 promoter activity, whereas knockdown of mutant p53 by small interfering RNA suppressed Notch1 expression, leading to the induction of cellular apoptosis. Moreover, curcumin-induced apoptosis was further enhanced by the knockdown of Notch1 or mutant p53, but it was decreased by the overexpression of active Notch1. Taken together, our results demonstrate, for the first time, that Notch1 is a transcriptional target of mutant p53 in breast cancer cells and suggest that the targeting of mutant p53 and/or Notch1 may be combined with a chemotherapeutic strategy to improve the response of breast cancer cells to curcumin.
Keywords
Apoptosis; Breast cancer cells; Curcumin; Mutant p53; Notch1;
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1 Wijnhoven SW, Speksnijder EN, Liu X, Zwart E, vanOostrom CT, Beems RB, Hoogervorst EM, Schaap MM, Attardi LD, Jacks T, van Steeg H, Jonkers J, de Vries A. Dominantnegative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage. Cancer Res. 2007;67:4648-4656.   DOI   ScienceOn
2 Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9:701-713.
3 Walerych D, Napoli M, Collavin L, Del Sal G. The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis. 2012;33:2007-2017.   DOI
4 Yugawa T, Handa K, Narisawa-Saito M, Ohno S, Fujita M, Kiyono T. Regulation of Notch1 gene expression by p53 in epithelial cells. Mol Cell Biol. 2007;27:3732-3742.   DOI   ScienceOn
5 Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I, Devgan V, Lieb J, Raffoul W, Hohl D, Neel V, Garlick J, Chiorino G, Dotto GP. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev. 2007;21:562-577.   DOI   ScienceOn
6 Alimirah F, Panchanathan R, Davis FJ, Chen J, Choubey D. Restoration of p53 expression in human cancer cell lines upregulates the expression of Notch1: implications for cancer cell fate determination after genotoxic stress. Neoplasia. 2007; 9:427-434.   DOI
7 Laws AM, Osborne BA. p53 regulates thymic Notch1 activation. Eur J Immunol. 2004;34:726-734.   DOI   ScienceOn
8 Bocchetta M, Miele L, Pass HI, Carbone M. Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells. Oncogene. 2003;22:81-89.   DOI   ScienceOn
9 Mehta SA, Christopherson KW, Bhat-Nakshatri P, Goulet RJ Jr, Broxmeyer HE, Kopelovich L, Nakshatri H. Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion. Oncogene. 2007;26:3329-3337.   DOI   ScienceOn
10 Kim SR, Park HJ, Bae YH, Ahn SC, Wee HJ, Yun I, Jang HO, Bae MK, Bae SK. Curcumin down-regulates visfatin expression and inhibits breast cancer cell invasion. Endocrinology. 2012; 153:554-563.   DOI
11 Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets. 2011;12:332-347.   DOI
12 Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer. 2006;106:2503-2513.   DOI   ScienceOn
13 Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. Adv Exp Med Biol. 2007;595:105-125.   DOI
14 Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199-225.   DOI   ScienceOn
15 Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Basic Clin Pharmacol Toxicol. 2007;101:427-433.   DOI   ScienceOn
16 Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J Exp Med. 2011;208:1931-1935.   DOI   ScienceOn
17 Liao S, Xia J, Chen Z, Zhang S, Ahmad A, Miele L, Sarkar FH, Wang Z. Inhibitory effect of curcumin on oral carcinoma CAL-27 cells via suppression of Notch-1 and NF-κB signaling pathways. J Cell Biochem. 2011;112:1055-1065.   DOI   ScienceOn
18 Li Y, Zhang J, Ma D, Zhang L, Si M, Yin H, Li J. Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling. FEBS J. 2012;279: 2247-2259.   DOI   ScienceOn
19 Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012;23:450-457.   DOI   ScienceOn
20 Fassl A, Tagscherer KE, Richter J, Berriel Diaz M, Alcantara Llaguno SR, Campos B, Kopitz J, Herold-Mende C, Herzig S, Schmidt MH, Parada LF, Wiestler OD, Roth W. Notch1 signaling promotes survival of glioblastoma cells via EGFRmediated induction of anti-apoptotic Mcl-1. Oncogene. 2012;31: 4698-4708.   DOI   ScienceOn
21 Simmons MJ, Serra R, Hermance N, Kelliher MA. NOTCH1 inhibition in vivo results in mammary tumor regression and reduced mammary tumorsphere-forming activity in vitro. Breast Cancer Res. 2012;14:R126. [Epub ahead of print]   DOI
22 Speiser J, Foreman K, Drinka E, Godellas C, Perez C, Salhadar A, Erşahin Ç, Rajan P. Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer. Int J Surg Pathol. 2012; 20:139-145.
23 Selivanova G. p53: fighting cancer. Curr Cancer Drug Targets. 2004;4:385-402.   DOI   ScienceOn
24 Horn HF, Vousden KH. Coping with stress: multiple ways to activate p53. Oncogene. 2007;26:1306-1316.   DOI   ScienceOn
25 Fontemaggi G, Dell'Orso S, Trisciuoglio D, Shay T, Melucci E, Fazi F, Terrenato I, Mottolese M, Muti P, Domany E, Del Bufalo D, Strano S, Blandino G. The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. Nat Struct Mol Biol. 2009;16:1086-1093.   DOI   ScienceOn
26 Molchadsky A, Rivlin N, Brosh R, Rotter V, Sarig R. p53 is balancing development, differentiation and de-differentiation to assure cancer prevention. Carcinogenesis. 2010;31:1501-1508.   DOI   ScienceOn
27 Bartek J, Iggo R, Gannon J, Lane DP. Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene. 1990;5:893-899.
28 Gurtner A, Starace G, Norelli G, Piaggio G, Sacchi A, Bossi G. Mutant p53-induced up-regulation of mitogen-activated protein kinase kinase 3 contributes to gain of function. J Biol Chem. 2010;285:14160-14169.   DOI   ScienceOn
29 Yeudall WA, Vaughan CA, Miyazaki H, Ramamoorthy M, Choi MY, Chapman CG, Wang H, Black E, Bulysheva AA, Deb SP, Windle B, Deb S. Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. Carcinogenesis. 2012;33:442-451.   DOI   ScienceOn
30 Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26: 2157-2165.   DOI   ScienceOn
31 Lara-Medina F, Perez-Sanchez V, Saavedra-Perez D, Blake- Cerda M, Arce C, Motola-Kuba D, Villarreal-Garza C, Gonzalez-Angulo AM, Bargalló E, Aguilar JL, Mohar A, Arrieta O. Triple-negative breast cancer in Hispanic patients: high prevalence, poor prognosis, and association with menopausal status, body mass index, and parity. Cancer. 2011;117:3658- 3669.   DOI   ScienceOn
32 Lim LY, Vidnovic N, Ellisen LW, Leong CO. Mutant p53 mediates survival of breast cancer cells. Br J Cancer. 2009; 101:1606-1612.   DOI   ScienceOn
33 Zang S, Chen F, Dai J, Guo D, Tse W, Qu X, Ma D, Ji C. RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer. Oncol Rep. 2010;23:893-899.