Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer

被引：26

作者：

Feng, Zhaoyi ^{[1
,2
,3
]}

Xu, Wandong ^{[1
]}

Zhang, Chenguang ^{[4
]}

Liu, Mengran ^{[1
]}

Wen, Hongwu ^{[1
]}

机构：

[1] Peking Univ, Dept Obstet & Gynecol, Hosp 1, Beijing 100034, Peoples R China

[2] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Immunol, Charlestown, MA 02129 USA

[3] Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA

[4] Capital Med Univ, Dept Med Genet, Beijing 100069, Peoples R China

来源：

ONCOTARGET | 2017年 / 8卷 / 05期

关键词：

epithelial ovarian carcinoma; Notch; Jagged1; NICD; gamma-secretase; HUMAN BREAST-CANCER; JAGGED1; EXPRESSION; ESTROGEN-RECEPTOR; ALZHEIMER-DISEASE; LEUKEMIA CELLS; CLEAVAGE; POOR; CARCINOMA; APOPTOSIS;

D O I：

10.18632/oncotarget.14152

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. Most patients are not diagnosed until the cancer is at an advanced stage with poor prognosis. Notch1 signaling pathway plays an oncogenic role in EOC. There have been few studies on enzymatic activity of gamma-secretase and the mechanism of how gamma-secretase inhibitor works on cancer cell. Here, we show that Jagged1 and NICD were highly expressed in ovarian carcinoma. The expressions of Notch1, Jagged1 and NICD in Notch1 pathway did not correlate with outcome in ovarian cancer. The enzymatic activity of g-secretase in ovarian cancer cell lines SKOV3, CAOV3 and ES2 is significantly higher than in normal ovarian epithelial cell line T29. DAPT (a gamma-secretase inhibitor) reduced the enzymatic activity of gamma-secretase, inhibited the proliferation, and increased the apoptosis in ovarian cancer cell lines. Hence, g-secretase inhibitor may become a highly promising novel therapeutic strategy against ovarian cancer in the field of precision medicine.

引用

页码：8215 / 8225

页数：11

共 32 条

[1]

Notch signaling: Cell fate control and signal integration in development [J].

Artavanis-Tsakonas, S ;

Rand, MD ;

Lake, RJ .

SCIENCE, 1999, 284 (5415) :770-776

[2]

Sequential combination therapy of ovarian cancer with cisplatin and γ-secretase inhibitor MK-0752 [J].

Chen, XiuXiu ;

Gong, LiHua ;

Ou, RongYing ;

Zheng, ZhenZhen ;

Chen, JinYan ;

Xie, FengFeng ;

Huang, XiaoXiu ;

Qiu, JianGe ;

Zhang, WenJi ;

Jiang, QiWei ;

Yang, Yang ;

Zhu, Hua ;

Shi, Zhi ;

Yan, XiaoJian .

GYNECOLOGIC ONCOLOGY, 2016, 140 (03) :537-544

[3]

γ-secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets [J].

Dorneburg, Carmen ;

Goss, Annika V. ;

Fischer, Matthias ;

Roels, Frederik ;

Barth, Thomas F. E. ;

Berthold, Frank ;

Kappler, Roland ;

Oswald, Franz ;

Siveke, Jens T. ;

Molenaar, Jan J. ;

Debatin, Klaus-Michael ;

Beltinger, Christian .

ONCOTARGET, 2016, 7 (39) :62799-62813

[4]

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain [J].

Dovey, HF ;

John, V ;

Anderson, JP ;

Chen, LZ ;

Andrieu, PD ;

Fang, LY ;

Freedman, SB ;

Folmer, B ;

Goldbach, E ;

Holsztynska, EJ ;

Hu, KL ;

Johnson-Wood, KL ;

Kennedy, SL ;

Kholedenko, D ;

Knops, JE ;

Latimer, LH ;

Lee, M ;

Liao, Z ;

Lieberburg, IM ;

Motter, RN ;

Mutter, LC ;

Nietz, J ;

Quinn, KP ;

Sacchi, KL ;

Seubert, PA ;

Shopp, GM ;

Thorsett, ED ;

Tung, JS ;

Wu, J ;

Yang, S ;

Yin, CT ;

Schenk, DB ;

May, PC ;

Altstiel, LD ;

Bender, MH ;

Boggs, LN ;

Britton, TC ;

Clemens, JC ;

Czilli, DL ;

Dieckman-McGinty, DK ;

Droste, JJ ;

Fuson, KS ;

Gitter, BD ;

Hyslop, PA ;

Johnstone, EM ;

Li, WY ;

Little, SP ;

Mabry, TE ;

Miller, FD ;

Ni, B .

JOURNAL OF NEUROCHEMISTRY, 2001, 76 (01) :173-181

[5]

TAN-1, THE HUMAN HOMOLOG OF THE DROSOPHILA NOTCH GENE, IS BROKEN BY CHROMOSOMAL TRANSLOCATIONS IN T-LYMPHOBLASTIC NEOPLASMS [J].

ELLISEN, LW ;

BIRD, J ;

WEST, DC ;

SORENG, AL ;

REYNOLDS, TC ;

SMITH, SD ;

SKLAR, J .

CELL, 1991, 66 (04) :649-661

[6]

CXCR4 expression in feline mammary carcinoma cells: evidence of a proliferative role for the SDF-1/CXCR4 axis [J].

Ferrari, Angelo ;

Petterino, Claudio ;

Ratto, Alessandra ;

Campanella, Chiara ;

Wurth, Roberto ;

Thellung, Stefano ;

Vito, Guendalina ;

Barbieri, Federica ;

Florio, Tullio .

BMC VETERINARY RESEARCH, 2012, 8

[7]

The Global Burden of Cancer 2013 Global Burden of Disease Cancer Collaboration [J].

Fitzmaurice, Christina ;

Dicker, Daniel ;

Pain, Amanda ;

Hamavid, Hannah ;

Moradi-Lakeh, Maziar ;

Maclntyre, Michael F. ;

Allen, Christine ;

Hansen, Gillian ;

Woodbrook, Rachel ;

Wolfe, Charles ;

Hamadeh, Randah R. ;

Moore, Ami ;

Werdecker, Andrea ;

Gessner, Bradford D. ;

Te Ao, Braden ;

McMahon, Brian ;

Karimkhani, Chante ;

Yu, Chuanhua ;

Cooke, Graham S. ;

Schwebel, David C. ;

Carpenter, David O. ;

Pereira, David M. ;

Nash, Denis ;

Kazi, Dhruv S. ;

De Leo, Diego ;

Plass, Dietrich ;

Ukwaja, Kingsley N. ;

Thurston, George D. ;

Jin, Kim Yun ;

Simard, Edgar P. ;

Mills, Edward ;

Park, Eun-Kee ;

Catala-Lopez, Ferran ;

DeVeber, Gabrielle ;

Gotay, Carolyn ;

Khan, Gulfaraz ;

Hosgood, H. Dean, III ;

Santos, Itamar S. ;

Leasher, Janet L. ;

Singh, Jasvinder ;

Leigh, James ;

Jonas, Jost B. ;

Sanabria, Juan ;

Beardsley, Justin ;

Jacobsen, Kathryn H. ;

Takahashi, Ken ;

Franklin, Richard C. ;

Ronfani, Luca ;

Montico, Marcella ;

Naldi, Luigi .

JAMA ONCOLOGY, 2015, 1 (04) :505-527

[8]

The Notch pathway in ovarian carcinomas and adenomas [J].

Hopfer, O ;

Zwahlen, D ;

Fey, MF ;

Aebi, S .

BRITISH JOURNAL OF CANCER, 2005, 93 (06) :709-718

[9]

Exacerbation of psoriatic skin lesions in a patient with Alzheimer disease receiving gamma-secretase inhibitor [J].

Hsu, Chao-Kai ;

Hsu, Chia-Chi ;

Lee, Julia Yu-Yun ;

Kuo, Yu-Min ;

Pai, Ming-Chyi .

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2013, 68 (02) :E46-E48

[10]

A sensitive and quantitative assay for measuring cleavage of presenilin substrates [J].

Karlström, H ;

Bergman, A ;

Lendahl, U ;

Näslund, J ;

Lundkvist, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (09) :6763-6766

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