Activation of RARα induces autophagy in SKBR3 breast cancer cells and depletion of key autophagy genes enhances ATRA toxicity

被引:26
作者
Brigger, D. [1 ,2 ]
Schlaefli, A. M. [1 ,2 ]
Garattini, E. [3 ]
Tschan, M. P. [1 ,2 ]
机构
[1] Univ Bern, Inst Pathol, Div Expt Pathol, CH-3010 Bern, Switzerland
[2] Univ Bern, Grad Sch Cellular & Biomed Sci, CH-3010 Bern, Switzerland
[3] IRCCS Ist Ric Farmacol Mario Negri, Lab Mol Biol, Milan, Italy
关键词
NEUTROPHIL DIFFERENTIATION; RETINOIDS; THERAPY; TRASTUZUMAB; DEGRADATION; INHIBITION; EXPRESSION; MECHANISM; DISEASE; NIX;
D O I
10.1038/cddis.2015.236
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
All-trans retinoic acid (ATRA), a pan-retinoic acid receptor (RAR) agonist, is, along with other retinoids, a promising therapeutic agent for the treatment of a variety of solid tumors. On the one hand, preclinical studies have shown promising anticancer effects of ATRA in breast cancer; on the other hand, resistances occurred. Autophagy is a cellular recycling process that allows the degradation of bulk cellular contents. Tumor cells may take advantage of autophagy to cope with stress caused by anticancer drugs. We therefore wondered if autophagy is activated by ATRA in mammary tumor cells and if modulation of autophagy might be a potential novel treatment strategy. Indeed, ATRA induces autophagic flux in ATRA-sensitive but not in ATRA-resistant human breast cancer cells. Moreover, using different RAR agonists as well as RAR alpha-knockdown breast cancer cells, we demonstrate that autophagy is dependent on RAR alpha activation. Interestingly, inhibition of autophagy in breast cancer cells by either genetic or pharmacological approaches resulted in significantly increased apoptosis under ATRA treatment and attenuated epithelial differentiation. In summary, our findings demonstrate that ATRA-induced autophagy is mediated by RAR alpha in breast cancer cells. Furthermore, inhibition of autophagy results in enhanced apoptosis. This points to a potential novel treatment strategy for a selected group of breast cancer patients where ATRA and autophagy inhibitors are applied simultaneously.
引用
收藏
页码:e1861 / e1861
页数:10
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