Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation

被引：117

作者：

Shi, Peiguo ^{[1
,2
]}

Liu, Wenjing ^{[1
,3
]}

Tala ^{[4
]}

Wang, Haixia ^{[1
,5
]}

Li, Fubing ^{[1
,2
,6
]}

Zhang, Hailin ^{[1
]}

Wu, Yingying ^{[1
,2
,7
]}

Kong, Yanjie ^{[1
]}

Zhou, Zhongmei ^{[1
]}

Wang, Chunyan ^{[7
]}

Chen, Wenlin ^{[8
]}

Liu, Rong ^{[1
]}

Chen, Ceshi ^{[1
]}

机构：

[1] Chinese Acad Sci, Kunming Inst Zool, Chinese Acad Sci & Yunnan Prov, Key Lab Anim Models & Human Dis Mech, Kunming, Yunnan, Peoples R China

[2] Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming, Yunnan, Peoples R China

[3] Kunming Univ Sci & Technol, Fac Life Sci & Technol, Kunming, Yunnan, Peoples R China

[4] Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin, Peoples R China

[5] Univ Sci & Technol China, Sch Life Sci, Hefei, Anhui, Peoples R China

[6] Univ Sci & Technol China, Med Ctr, Hefei, Anhui, Peoples R China

[7] Kunming Med Univ, Affiliated Hosp 1, Dept Pathol, Kunming, Yunnan, Peoples R China

[8] Kunming Med Univ, Canc Hosp, Kunming, Yunnan, Peoples R China

来源：

CELL DISCOVERY | 2017年 / 3卷

基金：

中国科学院西部之光基金;

关键词：

KLF5; metformin; PKA; stem cells; triple-negative breast cancer; DEPENDENT PROTEIN-KINASE; TRANSCRIPTION FACTOR; DIABETIC-PATIENTS; EPITHELIAL-CELLS; SURVIVAL; GROWTH; PHOSPHORYLATION; SYNTHASE; PROLIFERATION; STATISTICS;

D O I：

10.1038/celldisc.2017.10

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Kruppel-like factor 5 (KLF5) and its downstream target genes, such as Nanog and FGF-BP1, in TNBC cell lines. Metformin induced glycogen synthase kinase-3 beta (GSK3 beta)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3 beta, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3 beta-KLF5 signaling pathway.

引用

页数：13

共 50 条

[1]

[Anonymous], ONCOGENE

[2] Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer [J].

Bayraktar, Soley ;

Hernadez-Aya, Leonel F. ;

Lei, Xiudong ;

Meric-Bernstam, Funda ;

Litton, Jennifer K. ;

Hsu, Limin ;

Hortobagyi, Gabriel N. ;

Gonzalez-Angulo, Ana M. .

CANCER, 2012, 118 (05) :1202-1211

[3] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[4] PKA signaling drives mammary tumorigenesis through Src [J].

Beristain, A. G. ;

Molyneux, S. D. ;

Joshi, P. A. ;

Pomroy, N. C. ;

Di Grappa, M. A. ;

Chang, M. C. ;

Kirschner, L. S. ;

Prive, G. G. ;

Pujana, M. A. ;

Khokha, R. .

ONCOGENE, 2015, 34 (09) :1160-1173

[5] Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease [J].

Bianchini, Giampaolo ;

Balko, Justin M. ;

Mayer, Ingrid A. ;

Sanders, Melinda E. ;

Gianni, Luca .

NATURE REVIEWS CLINICAL ONCOLOGY, 2016, 13 (11) :674-690

[6] Cancer Statistics in China, 2015 [J].

Chen, Wanqing ;

Zheng, Rongshou ;

Baade, Peter D. ;

Zhang, Siwei ;

Zeng, Hongmei ;

Bray, Freddie ;

Jemal, Ahmedin ;

Yu, Xue Qin ;

He, Jie .

CA-A CANCER JOURNAL FOR CLINICIANS, 2016, 66 (02) :115-132

[7] TGF-β Tumor Suppression through a Lethal EMT [J].

David, Charles J. ;

Huang, Yun-Han ;

Chen, Mo ;

Su, Jie ;

Zou, Yilong ;

Bardeesy, Nabeel ;

Iacobuzio-Donahue, Christine A. ;

Massague, Joan .

CELL, 2016, 164 (05) :1015-1030

[8] Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers [J].

Deng, Xin-Sheng ;

Wang, Shuiliang ;

Deng, Anlong ;

Liu, Bolin ;

Edgerton, Susan M. ;

Lind, Stuart E. ;

Wahdan-Alaswad, Reema ;

Thor, Ann D. .

CELL CYCLE, 2012, 11 (02) :367-376

[9] Essential role of KLF5 transcription factor in cell proliferation and differentiation and its implications for human diseases [J].

Dong, Jin-Tang ;

Chen, Ceshi .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2009, 66 (16) :2691-2706

[10] (R(P))-CAMPS INHIBITS THE CAMP-DEPENDENT PROTEIN-KINASE BY BLOCKING THE CAMP-INDUCED CONFORMATIONAL TRANSITION [J].

DOSTMANN, WRG .

FEBS LETTERS, 1995, 375 (03) :231-234

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