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  • Accepted Manuscript br A natural

    2019-10-14

    ´╗┐Accepted Manuscript
    A natural product atalantraflavone inhibits non-small cell lung cancer progression via destabilizing Twist1
    Tao Yuan, Feng Ling, Yu Wang, Yin Teng
    To appear in: 
    Fitoterapia
    Please cite this article as: T. Yuan, F. Ling, Y. Wang, et al., A natural product atalantraflavone inhibits non-small cell lung cancer progression via destabilizing Twist1, Fitoterapia, https://doi.org/10.1016/j.fitote.2019.104275
    This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
    ACCEPTED MANUSCRIPT
    A natural product atalantraflavone inhibits non-small cell lung
    cancer progression via destabilizing Twist1
    Tao Yuana*, Feng Lingb*, Yu Wanga and Yin Tengc**
    aDepartment of Orthopedics, The Third Affiliated Hospital of Kunming Medical
    University, Tumor Hospital of Yunnan Province, Kunming, 650118, Yunnan, China
    bDepartment of Thoracic surgery, The Second Affiliated Hospital of Kunming
    cDepartment of Thoracic surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, China
    Running title: Atalantraflavone in lung cancer
    *Shared first authorship.
    **Correspondence: Yin Teng, M.D., Department of Thoracic surgery, The Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi street, Yunyan district, Guiyang, 550004, Guizhou, China
    ACCEPTED MANUSCRIPT
    ABSTRACT
    The non-small cell lung cancer (NSCLC) represents a malignant type of cancer worldwide. The atalantraflavone (AFL) is a natural product isolated from LY3009120 of Atalantia monophylla (L.) DC. However, the function of atalantraflavone in NSCLC is still elusive. In present work, we have unraveled a novel function of AFL in NSCLC. AFL significantly inhibited NSCLC cell viability and colony formation. AFL increased sub-G1 fraction and apoptotic rates in a dose-dependent manner. Furthermore, Twist-related protein 1 (Twist1) was identified as the target of AFL. The association between AFL and Twist1 markedly decreased the stability of Twist1 via elevated ubiquitin mediated proteasomal degradation. AFL induced NSCLC suppression was mediated by Twist1 as Twist1 overexpression could partially reverse the inhibitory effect of AFL on migration and metastasis. Furthermore, AFL could also sensitize NSCLC cells to cisplatin treatment and consistently impair NSCLC proliferation and metastasis. Our current data have identified a tumor suppressive function for AFL in NSCLC by increasing Twist1 degradation. Therefore, the anti-tumor activity of AFL might provide critical insight into pharmaceutic lung cancer intervention to overcome cisplatin resistance. Keywords: Atalantraflavone; NSCLC; Twist1
    ACCEPTED MANUSCRIPT
    1. Introduction
    The lung cancer belongs to one of the commonly diagnosed cancer-related mortality worldwide [1]. The 5- year survival for lung cancer patients is extremely low compared with majority of other cancers [2]. Lung cancer can be classified into two main histological categories: one is non-small cell lung cancer (NSCLC) which accounts for ~80% cases and the other denotes small cell lung cancer (SCLC) [3]. Patients which are diagnosed at early stage can benefit from surgery whereas lung cancer patients at late stage are usually subject to platinum-based therapies [4]. However, significant fraction of tumors becomes resistant to cisplatin and the therapeutic efficacy therefore keeps decreasing [5].