Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells.
Activation of Estrogen receptor (ER) α (α) promotes cell growth and influences the response of cancer cell to chemotherapeutic agents. However, the mechanism by which ERα activation antagonizes cells to chemotherapy-induced cytotoxicity remains unclear. Here, we investigated the effect of cisplatin on ERα activation. In addition, we examined whether down-regulation of ERα modulate cisplatin-mediated cytotoxicity using 2 human ovarian cancer cells (Caov-3 and Ovcar-3) transduced with ERα short hairpin RNA (shRNA). The proliferation assay showed that 17β-estradiol (E2) induced cell proliferation via activation of Akt and extracellular signal-regulated kinase (ERK) cascades, while shRNA mediated downregulation of ERα inhibited the cell proliferation. Immunoblot analysis revealed that cisplatin induced the phosphorylation of ERα at serine 118 via ERK cascade. Luciferase assay showed that cisplatin increases transcriptional activity of estrogen-responsive element (ERE). The E2-stimulated ERα activation attenuated cisplatin-induced cytotoxicity. Meanwhile, down-regulation of ERα inhibited E2-induced protective effect on cisplatin toxicity as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, Pretreatment with E2 followed by cisplatin decreased the expression of cleaved PARP, and increased the expression of anti-apoptotic protein Bcl-2. Collectively, our findings suggest that activation of ERα by E2 and cisplatin can induce platinum-resistance by increasing the expression of anti-apoptotic protein in ovarian cancer cells. Therefore, our findings provide valuable information that ERα might be a promising therapeutic target for platinum-resistant ovarian cancer.
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Sohei
S
Matsumura
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Tsuyoshi
T
Ohta
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Keiko
K
Yamanouchi
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Zhiyang
Z
Liu
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Takeshi
T
Sudo
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Takanobu
T
Kojimahara
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Manabu
M
Seino
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Megumi
M
Narumi
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Seiji
S
Tsutsumi
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Toshifumi
T
Takahashi
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Kazuhiro
K
Takahashi
b Osaka Medical Center and Research Institution for Maternal and Child Health , Osaka , Japan.
Hirohisa
H
Kurachi
a Department of Obstetrics and Gynecology , Yamagata University, Faculty of Medicine , Yamagata , Japan.
Satoru
S
Nagase
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D010984:Platinum / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D047628:Estrogen Receptor alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D010984:Platinum; D004958:Estradiol; D002945:Cisplatin
Cisplatin; ERK; drug resistance; estrogen receptor; ovarian cancer
J Biol Chem. 2002 Sep 6;277(36):33490-500
12087097
Gynecol Oncol. 2014 Jun;133(3):473-9
24674832
Gynecol Oncol. 1988 Jul;30(3):313-20
3391418
Mod Pathol. 2011 Mar;24(3):453-62
21102415
Gynecol Oncol. 2015 Nov;139(2):228-35
26383827
Oncogene. 2002 Oct 31;21(50):7680-9
12400010
Endocr Regul. 2013 Oct;47(4):189-99
24156707
Gynecol Oncol. 2009 May;113(2):205-9
19239974
Nihon Sanka Fujinka Gakkai Zasshi. 1989 Nov;41(11):1776-82
2687406
J Biol Chem. 1999 Oct 29;274(44):31648-54
10531373
Neoplasia. 2013 Nov;15(11):1262-71
24339738
Curr Treat Options Oncol. 2009 Apr;10(1-2):54-66
19381822
Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):865s-70s
15701879
Cell Signal. 2006 Dec;18(12):2089-97
16815674
Clin Cancer Res. 2008 Jul 15;14(14):4417-26
18579664
Oncogene. 2004 Jun 3;23 (26):4505-15
15048073
Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3:264-72
25597633
Endocrinology. 2006 Apr;147(4):1761-9
16396982
Int J Cancer. 2000 Jan 1;85(1):98-103
10585591
Cancer. 1989 Mar 15;63(6):1074-8
2917311
Cell. 1997 Oct 17;91(2):231-41
9346240
Annu Rev Biochem. 1994;63:451-86
7979245
Endocr Relat Cancer. 2000 Jun;7(2):85-93
10903526
Trends Pharmacol Sci. 2005 Mar;26(3):113-6
15749154
Clin Adv Hematol Oncol. 2005 Sep;3(9):723-36
16224447
Med Mol Morphol. 2014 Mar;47(1):43-53
23665993
Steroids. 2013 Jun;78(6):530-7
23402742
Semin Cancer Biol. 2014 Dec;29:40-50
25073112
Cancer Res. 2000 Nov 1;60(21):5988-94
11085518
Carcinogenesis. 2011 Apr;32(4):589-96
21173433
Cancer Res. 1999 Oct 15;59(20):5133-42
10537288
Curr Treat Options Oncol. 2002 Apr;3(2):131-41
12057076
Breast Cancer Res Treat. 2012 Aug;134(3):969-80
22374518
J Exp Clin Cancer Res. 2012 May 03;31:42
22553917
Cancer Lett. 2010 Apr 28;290(2):167-73
19796866
Oncogene. 2002 Jul 25;21(32):4921-31
12118371
Cancer Res. 1991 Aug 1;51(15):3867-73
1855205
Clin Cancer Res. 2009 May 1;15(9):2971-8
19383821
J Clin Endocrinol Metab. 2013 Jul;98(7):2775-82
23780377
Mol Cell Biol. 2000 Apr;20(8):2890-901
10733592