C-terminal HSP90 inhibitor L80 elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition

被引:37
作者
Cho, Tae-Min [1 ,2 ]
Kim, Ji Young [1 ]
Kim, Yoon-Jae [1 ,3 ]
Sung, Daeil [1 ,2 ]
Oh, Eunhye [1 ,2 ]
Jang, Seojin [1 ,2 ]
Farrand, Lee [4 ]
Van-Hai Hoang [5 ]
Cong-Truong Nguyen [5 ]
Ann, Jihyae [5 ]
Lee, Jeewoo [5 ]
Seo, Jae Hong [1 ,2 ]
机构
[1] Korea Univ, Coll Med, Dept Internal Med, Div Med Oncol, Seoul 152703, South Korea
[2] Korea Univ, Coll Med, Brain Korea 21 Program Biomed Sci, Seoul 152703, South Korea
[3] Korea Univ, Guro Hosp, Dept Biomed, Res Ctr, Seoul 08308, South Korea
[4] AusHlth Res, 65 Hardys Rd, Adelaide, SA 5032, Australia
[5] Seoul Natl Univ, Coll Pharm, Lab Med Chem, Seoul 08826, South Korea
基金
新加坡国家研究基金会;
关键词
C-terminal HSP90 inhibitor; L80; Triple-negative breast cancer; Cancer stem cells; STAT3; Metastasis; STEM-LIKE PROPERTIES; SHOCK-PROTEIN; 90; MATRIX METALLOPROTEINASES; SIGNALING PATHWAY; CELLS; EXPRESSION; ANGIOGENESIS; ACTIVATION; GROWTH; HEAT-SHOCK-PROTEIN-90;
D O I
10.1016/j.canlet.2019.01.029
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Triple-negative breast cancer (TNBC) is an aggressive heterogeneous disease with a divergent profile. It has an earlier tendency to form metastases and is associated with poor clinical outcomes due to the limited treatment options available. Heat-shock protein (HSP90) represents a potential treatment target as it promotes tumor progression and metastasis by modulating the maturation and stabilization of signal transduction proteins. We sought to investigate the efficacy of the C-terminal HSP90 inhibitor L80 on cell proliferation, breast cancer stem cell (BCSC)-like properties, tumor growth and metastasis. L80 suppressed cell viability and concomitantly inhibited AKT/MEK/ERK/JAK2/STAT3 signaling in TNBC cells but did not induce cytotoxicity in normal cells. L80 effectively targeted BCSC-like traits, together with significant reductions in the CD44high/CD24low-population, ALDH1 activity and mammosphere forming-ability. In support of the in vitro observations, L80 administration caused significant impairment in tumor growth, angiogenesis and distant metastases in an orthotopic allograft model with BCSC-enriched cells in vivo. These phenomena were associated with the suppression of BCSC-like characteristics and STAT3 dysfunction. Our findings highlight properties of the L80 compound that may be useful in suppressing metastatic TNBC.
引用
收藏
页码:141 / 153
页数:13
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