Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells

被引：88

作者：

Wang, Yujun ^{[1
]}

Han, Ernest ^{[1
]}

Xing, Quanhua ^{[1
]}

Yan, Jin ^{[1
]}

Arrington, Amanda ^{[1
]}

Wang, Charles ^{[2
]}

Tully, Dylan ^{[1
]}

Kowolik, Claudia M. ^{[2
]}

Lu, David M. ^{[2
]}

Frankel, Paul H. ^{[2
]}

Zhai, Jing ^{[2
]}

Wen, Wei ^{[1
]}

Hone, David ^{[2
]}

Yip, M. L. Richard ^{[2
]}

Yim, John H. ^{[1
]}

机构：

[1] Beckman Res Inst City Hope, Dept Surg, Duarte, CA 91010 USA

[2] Beckman Res Inst City Hope, Duarte, CA 91010 USA

来源：

CANCER LETTERS | 2015年 / 358卷 / 02期

关键词：

DDIT4; Baicalein; mTOR; IRF1; Cellular stress; DNA-DAMAGE RESPONSE; COLORECTAL-CANCER; REDD1; APOPTOSIS; LIPOXYGENASE; PATHWAY; P53; RESISTANCE; WOGONIN; STRESS;

D O I：

10.1016/j.canlet.2014.12.033

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Baicalein is a natural flavone that exhibits anticancer properties. Using microarrays we found that DDIT4 was the highest transcript induced by baicalein in cancer cells. We confirmed in multiple cancer cell lines large, dose-related expression of DDIT4 by quantitative RT-PCR and immunoblot, which correlates with growth inhibition. Time course experiments demonstrate that DDIT4 is rapidly inducible, with high expression maintained for several days in vitro. Induction of DDIT4 expression is p53 independent based on evaluation of p53 knockout cells. Since DDIT4 is known to inhibit mTORC1 activity we confirmed that baicalein suppresses phosphorylation of mTORC1 targets. Using RNA interference we demonstrate that mTORC1 activity and growth inhibition by baicalein is attenuated by knockdown of DDIT4. We furthermore demonstrate suppression of established tumors by baicalein in a mouse model of breast cancer with increased DDIT4 expression in the tumors. Finally, we demonstrate that baicalein upregulates DDIT4 and causes mTORC1 and growth inhibition in platinum resistant cancer cells in marked contrast to platinum chemotherapy treatment. These studies demonstrate that baicalein inhibits mTORC1 through DDIT4 expression, and may be useful in cancer chemotherapy and chemoprevention. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

引用

页码：170 / 179

页数：10

共 27 条

[11] IRF-1 transcriptionally upregulates PUMA, which mediates the mitochondrial apoptotic pathway in IRF-1-induced apoptosis in cancer cells [J].

Gao, J. ;

Senthil, M. ;

Ren, B. ;

Yan, J. ;

Xing, Q. ;

Yu, J. ;

Zhang, L. ;

Yim, J. H. .

CELL DEATH AND DIFFERENTIATION, 2010, 17 (04) :699-709

[12] Identification of a Natural Compound by Cell-Based Screening That Enhances Interferon Regulatory Factor-1 Activity and Causes Tumor Suppression [J].

Gao, Jinbo ;

Wang, Yujun ;

Xing, Quanhua ;

Yan, Jin ;

Senthil, Maheswari ;

Akmal, Yasir ;

Kowolik, Claudia M. ;

Kang, Julia ;

Lu, David M. ;

Zhao, Ming ;

Lin, Zhixiu ;

Cheng, Christopher H. K. ;

Yip, M. L. Richard ;

Yim, John H. .

MOLECULAR CANCER THERAPEUTICS, 2011, 10 (10) :1774-1783

[13] Baicalein induces a dual growth arrest by modulating multiple cell cycle regulatory molecules [J].

Hsu, SL ;

Hsieh, YC ;

Hsieh, WC ;

Chou, CJ .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2001, 425 (03) :165-171

[14] A Phase I Study of the Chinese Herbal Medicine PHY906 as a Modulator of Irinotecan-based Chemotherapy in Patients with Advanced Colorectal Cancer [J].

Kummar, Shivaani ;

Copur, M. Sitki ;

Rose, Michal ;

Wadler, Scott ;

Stephenson, Joe ;

O'Rourke, Mark ;

Brenckman, Wayne ;

Tilton, Robert ;

Liu, Shwu-Huey ;

Jiang, Zaoli ;

Su, Tahmun ;

Cheng, Yung-chi ;

Chu, Edward .

CLINICAL COLORECTAL CANCER, 2011, 10 (02) :85-96

[15] New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin [J].

Li-Weber, Min .

CANCER TREATMENT REVIEWS, 2009, 35 (01) :57-68

[16] Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway [J].

Pamment, J ;

Ramsay, E ;

Kelleher, M ;

Dornan, D ;

Ball, KL .

ONCOGENE, 2002, 21 (51) :7776-7785

[17] Ectopic expression of interferon regulatory factor-1 promotes human breast cancer cell death and results in reduced expression of survivin [J].

Pizzoferrato, E ;

Liu, Y ;

Gambotto, A ;

Armstrong, MJ ;

Stang, MT ;

Gooding, WE ;

Alber, SM ;

Shand, SH ;

Watkins, SC ;

Storkus, WJ ;

Yim, JH .

CANCER RESEARCH, 2004, 64 (22) :8381-8388

[18]

SCHMIDT W, 1993, CANCER RES, V53, P799

[19] SELECTIVE-INHIBITION OF PLATELET LIPOXYGENASE BY BAICALEIN [J].

SEKIYA, K ;

OKUDA, H .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1982, 105 (03) :1090-1095

[20]

Shieh DE, 2000, ANTICANCER RES, V20, P2861

← 1 2 3 →