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Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes.

ABSTRACT: Psoriasis is a chronic skin disease characterized by hyperproliferation and impaired differentiation of epidermal keratinocytes accompanied by increased inflammation, suggesting that molecules with antiproliferation and anti-inflammatory abilities may be effective for its treatment. One of the key steps in regulating cell proliferation is DNA replication initiation, which relies on prereplication complex (pre-RC) assembly on chromatin. CDC6 is an essential regulator of pre-RC assembly and DNA replication in eukaryotic cells, but its role in proliferation of keratinocytes and psoriasis is unknown. Here we examined CDC6 expression in psoriatic skin and evaluated its function in the proliferation of human keratinocytes. CDC6 expression is upregulated in epidermal cells in psoriatic lesions and it could be induced by IL-22/STAT3 signaling, a key signaling pathway involved in the pathogenesis of psoriasis, in keratinocytes. Depletion of CDC6 leads to decreased proliferation of keratinocytes. We also revealed that berberine (BBR) could inhibit CDK4/6-RB-CDC6 signaling in keratinocytes, leading to reduced proliferation of keratinocytes. The mechanism of antiproliferation effects of BBR is through the repression of JAK1, JAK2, and TYK2, which in turn inhibits activation of STAT3. Finally, we demonstrated that BBR could inhibit imiquimod-induced psoriasis-like skin lesions and upregulation of CDC6 and p-STAT3 in mice. Collectively, our findings indicate that BBR inhibits CDC6 expression and proliferation in human keratinocytes by interfering the JAK-STAT3 signaling pathway. Thus, BBR may serve as a potential therapeutic option for patients with psoriasis.

SUBMITTER: Sun S

PROVIDER: S-EPMC6426889 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes.

Sun Shuna S Zhang Xiaojie X Xu Mengru M Zhang Fang F Tian Fei F Cui Jianfeng J Xia Yangyang Y Liang Chenxi C Zhou Shujie S Wei Haifeng H Zhao Hui H Wu Guojing G Xu Bohan B Liu Xiaochen X Yang Guanqun G Wang Qinzhou Q Zhang Lei L Gong Yaoqin Y Shao Changshun C Zou Yongxin Y

Cell death & disease 20190320 4

Psoriasis is a chronic skin disease characterized by hyperproliferation and impaired differentiation of epidermal keratinocytes accompanied by increased inflammation, suggesting that molecules with antiproliferation and anti-inflammatory abilities may be effective for its treatment. One of the key steps in regulating cell proliferation is DNA replication initiation, which relies on prereplication complex (pre-RC) assembly on chromatin. CDC6 is an essential regulator of pre-RC assembly and DNA re ...[more]

PMID: 30894513

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Project description:Multiple myeloma (MM) is a hematological cancer causing from accumulated abnormal plasma cells. STAT3 overexpression in MM appears to be mediated by a variety of factors, and it may be associated with an adverse prognosis and play a role in microenvironment-dependent treatment resistance. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. It is an oral, multitargeted inhibitor of receptor tyrosine kinases, including BCR-ABL, c-KIT, PDGFR, and Src family kinases. However, little is known about the effects of radotinib on multiple myeloma cells. However, little is known about the effects of radotinib on multiple myeloma cells. But even tinip almost not known about the impact of multiple myeloma cells. Moreover, nothing is known about how it affects STAT3 and JAK2. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Herein, Moreover, nothing is known about how it. Moreover, not all is known about how the affects STAT3 and JAK2. We investigated the effect of radotinib on the STAT3 signaling pathway in MM cells, including several MM cell lines and mouse models. So we investigated the effect of radotinib on MM cells, including several MM cell lines and mouse models. Interestingly, radotinib induced apoptosis, and inhibited cell proliferation in MM cells including RPMI-8226, MM.1S, U266B1, and IM-9 cells. Moreover, radotinib treatment significantly increased the number Annexin V-positive cells and G0/G1-phase cells. In addition, radotinib treatment in various MM cells strongly suppressed the activity and expression of STAT3 and JAK2 proteins. We also observed that diverse proteins related to the STAT3 signaling pathway, including c-Myc, Bcl-xL, Mcl-1, cyclin D1 and cyclin D3, were powerfully inhibited by radotinib treatment in MM cells. Furthermore, radotinib significantly suppressed MM cell growth in a xenograft animal model using IM-9 cells. In conclusion, radotinib may play an important role as a candidate agent for MM treatment.

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Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes.

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Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes.

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