Abstract
There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERRα) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERRα by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins related to endoplasmic reticulum (ER) stress such as ATF4/6, XBT-1 and CHOP. It also increases the expression of growth inhibition related proteins such as p53 and p21. Further, XCT-790 can increase the generation of reactive oxygen species (ROS) in TNBC cells mainly through inhibition of SOD1/2. While ROS scavenger NAC abolishes XCT-790 induced ER-stress and growth arrest. XCT-790 treatment can rapidly activate the signal molecules including ERK1/2, p38-MAPK, JNK, Akt, p65, and IκBα, while NAC attenuates effects of XCT-790 induced phosphorylation of ERK1/2, p38-MAPK and Akt. Further, the inhibitors of ERK1/2, JNK, Akt, and NF-κB attenuate XCT-790 induced ROS generation. These data suggest that AKT/ROS and ERK/ROS positive feedback loops, NF-κB/ROS, and ROS/p38-MAPK, are activated in XCT-790 treated TNBC cells. In vivo experiments show that XCT-790 significantly suppresses the growth of MDA-MB-231 xenograft tumors, which is associated with up regulation of p53, p21, ER-stress related proteins while down regulation of bcl-2. The present discovery makes XCT-790 a promising candidate drug and lays the foundation for future development of ERRα-based therapies for TNBC patients.
Highlights
The estrogen-related receptor alpha (ERRα), a member of the nuclear hormone receptor super family of transcription factors, can regulate the energy metabolism and mitochondrial biogenesis [1]
Western blot analysis revealed that the expression of ERRα was significantly silenced by si-ERRα while not XCT-790 (Figure 1B)
We examined the expressions of estrogen receptor (ER) stress-related proteins such as activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), X-box binding proteins 1 (XBP-1), and C/EBP-homologous protein (CHOP) in XCT-790-treated triplenegative breast cancer (TNBC) cells
Summary
The estrogen-related receptor alpha (ERRα), a member of the nuclear hormone receptor super family of transcription factors, can regulate the energy metabolism and mitochondrial biogenesis [1]. Previous studies revealed that the expression of ERRα was correlate with increased risk of recurrence and adverse clinical outcomes of breast cancer patients via a ER status independent manner [3, 4]. High ERRα expression has been reported in breast, ovarian and prostate cancers, which is correlated with poor prognosis [3, 7]. ERRα is involved in angiogenesis and response to hypoxia of solid tumors [8, 9]. These rapidly accumulating evidences suggest that ERRα emerges as a transcriptional metabolic regulator that promotes cancer development [10, 11]
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