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Biochem Biophys Res Commun. 2017 Sep 9;491(1):159-165. doi: 10.1016/j.bbrc.2017.07.067. Epub 2017 Jul 12.

Inhibition of IL-6/STAT3 signaling in human cancer cells using Evista.

Author information

1
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
2
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; Division of Cardiology, Tianjin First Center Hospital, Tianjin, PR China.
3
Division of Gastroenterology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
4
Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
5
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
6
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
7
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. Electronic address: lujiagao@tjh.tjmu.edu.cn.
8
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. Electronic address: linlee271227@163.com.

Abstract

Persistent activation of IL-6/STAT3 signaling pathway has been frequently detected in human cancer including breast cancer, colon cancer and multiple myeloma. IL-6/STAT3 can be a promising target for cancer prevent and treatment. However, few STAT3 inhibitors with high efficiency, specificity and safety is available for present clinical cancer therapy. Evista (Raloxifene·HCl) is known as selective estrogen receptor modulator which has been used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer. Our previous study found that Raloxifene inhibited IL-6/GP130 interaction, resulting in blockade of STAT3 phosphorylation. In our present study, we examined the effect on IL-6/GP130/STAT3 signaling pathway and cancer cell viability with Evista. We first demonstrated Evista inhibited constitutive activation of STAT3 in breast cancer cell line MDB-MB-231, colon cancer cell line HCT116 and multiple myeloma cancer cell line U266. Evista also inhibited phosphorylation of STAT3 induced by IL-6 in MCF-7, HT29 and MM.1S cancer cell lines. Induction of apoptosis was exerted in MDA-MB-231, HCT116 and U266 as evidenced by increased caspase-3 cleavage. However, Evista did not inhibit STAT1, STAT2, STAT4 or STAT6 phosphorylation elicited by IFN-α, IFN-γ and IL-4, nor phosphorylation of STAT3 induced by LIF in MCF-7 cell lines. Evista attenuated STAT3 phosphorylation, decreased STAT3 transcriptional activity but much less in pGL3 and AP1 transcriptional luciferase activity, and decreased cell viability in vitro. These results suggest that it may be possible for Evista to emerge as a chemoprevention agent for breast cancer and other cancers such as colon cancer or multiple myeoloma by targeting IL-6/STAT3 signaling.

KEYWORDS:

Breast cancer; Colon cancer; Multiple myeloma; Raloxifene; STAT3

PMID:
28711499
DOI:
10.1016/j.bbrc.2017.07.067
[Indexed for MEDLINE]

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