Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1α and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro

被引:28
作者
Tanaka, Tomokazu [1 ]
Ikegami, Yuichi [1 ]
Nakazawa, Harumasa [1 ,2 ]
Kuriyama, Naohide [1 ,2 ]
Oki, Miwa [3 ]
Hanai, Jun-Ichi [3 ]
Sukhatme, Vikas P. [3 ]
Kaneki, Masao [1 ,2 ]
机构
[1] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA
[2] Shriners Hosp Children, Boston, MA USA
[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Dept Med,Div Nephrol, Boston, MA USA
基金
美国国家卫生研究院;
关键词
FARNESYL TRANSFERASE INHIBITOR; TRANSCRIPTION FACTOR SNAIL; TO-MESENCHYMAL TRANSITION; ACUTE MYELOID-LEUKEMIA; PHASE-II TRIAL; TUMOR-GROWTH; TIPIFARNIB; R115777; METASTASIS; ACTIVATION;
D O I
10.1002/jcp.25411
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The aggressiveness of triple-negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self-renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression is associated with aggressiveness of cancer. Nonetheless, how HIF-1 alpha expression is regulated and how HIF-1 alpha induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF-1 alpha expression has not yet been studied. Here, we show that clinically relevant low-dose FTI, tipifarnib (300 nM), decreased HIF-1 alpha expression, migration and tumorsphere formation in human MDA-MB-231 TNBC cells under a normoxic condition. In contrast, the low-dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA-MB 231 cells. Tipifarnib-induced decrease in HIF-1 alpha expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E-cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF-1 alpha-Snail pathway. (C) 2016 Wiley Periodicals, Inc.
引用
收藏
页码:192 / 201
页数:10
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