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      Cordycepin Inhibits Human Gestational Choriocarcinoma Cell Growth by Disrupting Centrosome Homeostasis

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          Abstract

          Introduction

          Human gestational choriocarcinoma, a type of gestational trophoblastic disease, occurs after miscarriage, abortion, ectopic pregnancy, or molar pregnancy. Despite recent advances in the mechanism of anticancer drugs that induce human gestational choriocarcinoma apoptosis or block its growth, new therapeutic approaches are needed to be established. Cordycepin is an active anti-cancer component extracted from Cordyceps sinensis. It prevents cell proliferation both in vitro and in vivo.

          Materials and Methods

          Here, we examined cell growth by counting cell numbers, and performing a flow cytometry assay and EdU incorporation assay. Centrosome and cytoskeleton-related structures were observed by immunofluorescence assay. The DNA damage-related signaling was examined by Western blot assay.

          Results

          Here, we showed that cordycepin inhibited human gestational choriocarcinoma cell proliferation and induced cell death. In addition, treatment with cordycepin activated DNA-PK and ERK, thus inducing centrosome amplification and aberrant mitosis. These amplified centrosomes also disrupted microtubule arrays and actin networks, thus leading to defective cell adhesion. Furthermore, cordycepin induced autophagy for triggering cell death.

          Conclusion

          Thus, our study demonstrates that cordycepin inhibits cell proliferation and disrupts the cytoskeleton by triggering centrosome amplification.

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          Most cited references 36

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          Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions.

           M-D Schaller (2010)
          Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are related tyrosine kinases that have important cellular functions, primarily through regulation of the cytoskeleton. Recent studies have identified multiple molecular mechanisms that regulate cytoskeletal responses, and have provided important and exciting insights into how FAK and Pyk2 control cellular processes such as cell migration. Equally exciting are reports of novel and originally unanticipated functions of these kinases, providing the groundwork for future avenues of investigation. This Commentary summarizes some of these recent discoveries that are relevant to the control of biological responses of the cell.
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            DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?

            The DNA damage signalling pathway is a core element of the cellular response to genotoxic insult, and its components play key roles in defending against neoplastic transformation. Recent work has indicated that the human ATM and ATR proteins, and their yeast homologues, are intimately involved in sensing DNA damage, suggesting parallels with the DNA double-strand break repair enzyme DNA-PK.
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              The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14.

              ULK1 (unc-51 like autophagy activating kinase 1), the key mediator of MTORC1 signaling to autophagy, regulates early stages of autophagosome formation in response to starvation or MTORC1 inhibition. How ULK1 regulates the autophagy induction process remains elusive. Here, we identify that ATG13, a binding partner of ULK1, mediates interaction of ULK1 with the ATG14-containing PIK3C3/VPS34 complex, the key machinery for initiation of autophagosome formation. The interaction enables ULK1 to phosphorylate ATG14 in a manner dependent upon autophagy inducing conditions, such as nutrient starvation or MTORC1 inhibition. The ATG14 phosphorylation mimics nutrient deprivation through stimulating the kinase activity of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex and facilitates phagophore and autophagosome formation. By monitoring the ATG14 phosphorylation, we determined that the ULK1 activity requires BECN1/Beclin 1 but not the phosphatidylethanolamine (PE)-conjugation machinery and the PIK3C3 kinase activity. Monitoring the phosphorylation also allowed us to identify that ATG9A is required to suppress the ULK1 activity under nutrient-enriched conditions. Furthermore, we determined that ATG14 phosphorylation depends on ULK1 and dietary conditions in vivo. These results define a key molecular event for the starvation-induced activation of the ATG14-containing PtdIns3K complex by ULK1, and demonstrate hierarchical relations between the ULK1 activation and other autophagy proteins involved in phagophore formation.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                27 July 2020
                2020
                : 14
                : 2987-3000
                Affiliations
                [1 ]Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University , Tainan, Taiwan
                [2 ]Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University , Tainan, Taiwan
                [3 ]Department of Obstetrics and Gynecology, An Nan Hospital, China Medical University , Tainan, Taiwan
                [4 ]Institute of Biomedical Sciences, Academia Sinica , Taipei, Taiwan
                [5 ]School of Chinese Medicine for Post-Baccalaureate, I-Shou University , Kaohsiung, Taiwan
                [6 ]Department of Chinese Medicine, E-Da Cancer Hospital , Kaohsiung, Taiwan
                [7 ]Department of Anesthesia & Medical Research, An Nan Hospital, China Medical University , Tainan, Taiwan
                [8 ]Graduate Institute of Medical Sciences, Chang Jung Christian University Tainan , Tainan, Taiwan
                [9 ]Institute of Medical Research, China Medical University , Taichung, Taiwan
                Author notes
                Correspondence: Edmund Cheung So; Bu-Miin Huang Tel +886-6-3553111 ext.1517; +886-6-2353535 ext. 5337Fax +886-6-3553111; +886-6-2093007 Email edmundsotw@gmail.com; bumiin@mail.ncku.edu.tw
                [*]

                These authors contributed equally to this work

                Article
                252401
                10.2147/DDDT.S252401
                7394508
                © 2020 Wang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 8, References: 41, Pages: 14
                Categories
                Original Research

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