title: Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide.
abstract: Arsenic trioxide (As2O3), a component of traditional Chinese medicine, has been used successfully for the treatment of acute promyelocytic leukemia (APL), and As2O3 is of potential therapeutic value for the treatment of other promyelocytic malignancies and some solid tumors including breast cancer. However, the precise molecular mechanisms through which As2O3 induces cell cycle arrest and apoptosis in solid tumors have not been clearly understood. The goal of our study is to gain insight into the general biological processes and molecular functions that are altered by As2O3 treatment in MCF-7 breast cancer cells and to identify the key signaling processes that are involved in the regulation of these physiological effects. In the present study, MCF-7 cells were treated with 5 μM As2O3, and the differential gene expression was then analyzed by DNA microarray. The results showed that As2O3 treatment changed the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis. Notably, As2O3 treatment increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27. Interestingly, knocking down p21 or p27 individually did not alter As2O3-induced apoptosis and cell cycle arrest; however, the simultaneous down-regulation of both p21 and p27 resulted in attenuating of G1, G2/M arrest and reduction in apoptosis, thus indicating that p21 and p27 as the primary molecular targets of As2O3 against breast cancer. Overall, our results provide new insights into As2O3-related signaling activities, which may facilitate the development of As2O3-based anticancer strategies and/or combination therapies against solid tumors.
authors.affiliation: Research Center, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, 710038, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Wei
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Ren
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.forename: Yuan
authors.initials: Y
authors.lastname: Han
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002469:Cell Separation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects*; D018816:Genes, cdc; D006801:Humans; D020287:In Situ Nick-End Labeling; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000494:pharmacology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010087:Oxides; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077237:Arsenic Trioxide
references.citation: Cancer Res. 2004 Dec 1;64(23):8604-12
references.pmid: 15574767
references.citation: Nat Med. 1997 Feb;3(2):227-30
references.pmid: 9018244
references.citation: Zhonghua Wai Ke Za Zhi. 2007 Apr 1;45(7):473-5
references.pmid: 17686306
references.citation: J Clin Pathol. 2003 Mar;56(3):214-20
references.pmid: 12610102
references.citation: Breast Cancer Res Treat. 2006 Jun;97(3):275-83
references.pmid: 16344916
references.citation: Nature. 2000 Aug 17;406(6797):742-7
references.pmid: 10963601
references.citation: Cancer Res. 2005 Feb 1;65(3):967-71
references.pmid: 15705897
references.citation: Cancer Gene Ther. 2005 Jan;12(1):84-9
references.pmid: 15472715
references.citation: Leuk Res. 2004 Sep;28(9):891-900
references.pmid: 15234563
references.citation: Cancer Res. 2007 Dec 1;67(23):11186-94
references.pmid: 18056443
references.citation: Int J Cancer. 2001 May 1;92(3):370-3
references.pmid: 11291073
references.citation: J Carcinog. 2005 Apr 20;4(1):7
references.pmid: 15842733
references.citation: Cancer Cell. 2003 Jan;3(1):51-62
references.pmid: 12559175
references.citation: Clin Exp Pharmacol Physiol. 2005 Dec;32(12):1042-8
references.pmid: 16445569
references.citation: J Mammary Gland Biol Neoplasia. 2004 Jan;9(1):67-80
references.pmid: 15082919
references.citation: Breast Cancer Res. 2003;5(6):R242-9
references.pmid: 14580260
references.citation: Clin Cancer Res. 1996 Sep;2(9):1591-9
references.pmid: 9816338
references.citation: Cancer Res. 2006 Dec 15;66(24):11623-31
references.pmid: 17178856
references.citation: Curr Opin Cell Biol. 2003 Jun;15(3):345-50
references.pmid: 12787778
references.citation: Cell Stem Cell. 2007 Jun 7;1(1):87-99
references.pmid: 18371338
references.citation: J Clin Oncol. 2001 Sep 15;19(18):3852-60
references.pmid: 11559723
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Biol Chem. 2004 May 7;279(19):19643-8
references.pmid: 14990569
references.citation: Breast Cancer Res Treat. 2002 May;73(1):61-73
references.pmid: 12083632
references.citation: Nat Rev Cancer. 2004 Sep;4(9):665-76
references.pmid: 15343273
references.citation: BMC Cancer. 2008 Nov 23;8:340
references.pmid: 19025611
references.citation: J Cell Biochem. 2004 Sep 1;93(1):173-87
references.pmid: 15352174