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Berberine binds RXR? to suppress ?-catenin signaling in colon cancer cells.

ABSTRACT: Berberine, an isoquinoline alkaloid, is a traditional oriental medicine used to treat diarrhea and gastroenteritis. Recently, we reported that it could inhibit the growth of intestinal polyp in animals and in patients with the familial adenomatous polyposis by downregulating ?-catenin signaling. However, the intracellular target mediating the effects of berberine remains elusive. Here, we provide evidence that berberine inhibits ?-catenin function via directly binding to a unique region comprising residues Gln275, Arg316 and Arg371 in nuclear receptor retinoid X receptor alpha (RXR?), where berberine concomitantly binding to and synergistically activating RXR? with 9-cis-retinoic acid (9-cis-RA), a natural ligand binding to the classical ligand-binding pocket of RXR?. Berberine binding promotes RXR? interaction with nuclear ?-catenin, leading to c-Cbl mediated degradation of ?-catenin, and consequently inhibits the proliferation of colon cancer cells. Furthermore, berberine suppresses the growth of human colon carcinoma xenograft in nude mice in an RXR?-dependent manner. Together, our study not only identifies RXR? as a direct protein target for berberine but also dissects their binding mode and validates that berberine indeed suppresses ?-catenin signaling and cell growth in colon cancer via binding RXR?, which provide new strategies for the design of new RXR?-based antitumor agents and drug combinations.

SUBMITTER: Ruan H

PROVIDER: S-EPMC5735301 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells.

Ruan H H Zhan Y Y YY Hou J J Xu B B Chen B B Tian Y Y Wu D D Zhao Y Y Zhang Y Y Chen X X Mi P P Zhang L L Zhang S S Wang X X Cao H H Zhang W W Wang H H Li H H Li H H Su Y Y Zhang X K XK Hu T T

Oncogene 20170828 50

Berberine, an isoquinoline alkaloid, is a traditional oriental medicine used to treat diarrhea and gastroenteritis. Recently, we reported that it could inhibit the growth of intestinal polyp in animals and in patients with the familial adenomatous polyposis by downregulating β-catenin signaling. However, the intracellular target mediating the effects of berberine remains elusive. Here, we provide evidence that berberine inhibits β-catenin function via directly binding to a unique region comprisi ...[more]

PMID: 28846104

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Project description:BackgroundMesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.MethodsThe effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.ResultsOur results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.ConclusionsThe eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.

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Berberine binds RXR? to suppress ?-catenin signaling in colon cancer cells.

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Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells.

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