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      Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway

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          Abstract

          Cell division cycle 37 (Cdc37) is an important partner for heat shock protein 90 ( HSP90), assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulates cell survival in colorectal carcinoma ( CRC) remain unclear. Here, we investigated the expression of Cdc37 and its clinical significance in CRC, and systematically explored the role and the underlying mechanism of Cdc37 in CRC cell survival both in vitro and in vivo. Our results showed that Cdc37 was remarkably up‐regulated in CRC, which facilitated cell survival mainly by promoting cell proliferation, G1‐S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of cyclin‐dependent kinase 4 ( CDK4) to activate the retinoblastoma 1 ( RB1) signaling pathway, followed by increased expression of Bcl‐2 and Bcl‐ xL, which ultimately promoted cell survival in CRC. Moreover, knockdown of CDK4 reversed the Cdc37‐mediated effect in promoting the progression of CRC. Our findings showed that Cdc37 played a critical role in promoting CRC cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patients.

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          A comprehensive modular map of molecular interactions in RB/E2F pathway

          We present, here, a detailed and curated map of molecular interactions taking place in the regulation of the cell cycle by the retinoblastoma protein (RB/RB1). Deregulations and/or mutations in this pathway are observed in most human cancers. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner 3.5 software and converted into BioPAX 2.0 pathway description format. In the current state the map contains 78 proteins, 176 genes, 99 protein complexes, 208 distinct chemical species and 165 chemical reactions. Overall, the map recapitulates biological facts from approximately 350 publications annotated in the diagram. The network contains more details about RB/E2F interaction network than existing large-scale pathway databases. Structural analysis of the interaction network revealed a modular organization of the network, which was used to elaborate a more summarized, higher-level representation of RB/E2F network. The simplification of complex networks opens the road for creating realistic computational models of this regulatory pathway.
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            Silencing the cochaperone CDC37 destabilises kinase clients and sensitises cancer cells to HSP90 inhibitors

            The cochaperone CDC37 promotes association of HSP90 with the protein kinase subset of client proteins to maintain their stability and signalling functions. HSP90 inhibitors induce depletion of clients, which include several oncogenic kinases. We hypothesised that the targeting of CDC37 using siRNAs would compromise the maturation of these clients and increase the sensitivity of cancer cells to HSP90 inhibitors. Here we show that silencing of CDC37 in human colon cancer cells diminished association of kinase clients with HSP90 and reduced levels of the clients ERBB2, CRAF, CDK4 and CDK6, as well as phosphorylated AKT. CDC37 silencing promoted the proteasome-mediated degradation of kinase clients, suggesting a degradation pathway independent from HSP90 binding. Decreased cell signalling through kinase clients was also demonstrated by reduced phosphorylation of downstream substrates and colon cancer cell proliferation was subsequently reduced by inhibition of the G1/S-phase transition. Furthermore, combining CDC37 silencing with the HSP90 inhibitor 17-AAG induced more extensive and sustained depletion of kinase clients and potentiated cell cycle arrest and apoptosis. These results support an essential role for CDC37 in concert with HSP90 in maintaining oncogenic protein kinase clients and endorse the therapeutic potential of targeting CDC37 in cancer.
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              Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1

              Phosphatidylinositol-3-kinase (PI3K) signaling is constitutive in most human cancers. Selective inhibition of PI3Kδ (p110δ) by GS-1101 has emerged as a promising therapy in chronic lymphocytic leukemia and indolent lymphomas. In aggressive non-Hodgkin lymphomas such as mantle cell lymphoma (MCL), however, efficacy has been observed, but the extent and duration of tumor control is modest. To determine if tumor killing by GS-1101 is cell cycle-dependent, we show in primary MCL cells by whole-transcriptome sequencing that, despite aberrant expression and recurrent mutations in Cyclin D1, mutations are rare in coding regions of CDK4, RB1 and other genes that control G1-S cell cycle progression or PI3K/AKT signaling. PI3Kδ is the predominant PI3K catalytic subunit expressed, and inhibition by GS-1101 transiently inhibits AKT phosphorylation but not proliferation in MCL cells. Induction of prolonged early G1-arrest (pG1) by selective inhibition of CDK4/CDK6 with PD 0332991 amplifies and sustains PI3Kδ inhibition, which leads to robust apoptosis. Accordingly, inhibition of PI3Kδ induces apoptosis of primary MCL tumor cells once they have ceased to cycle ex vivo, and this killing is enhanced by PD 0332991 inhibition of CDK4/CDK6. PIK3IP1, a negative PI3K regulator, appears to mediate pG1 sensitization to PI3K inhibition; it is markedly reduced in MCL tumor cells compared with normal peripheral B cells, profoundly induced in pG1 and required for pG1 sensitization to GS-1101. Thus, the magnitude and duration of PI3K inhibition and tumor killing by GS-1101 is pG1-dependent, suggesting induction of pG1 by CDK4/CDK6 inhibition as a strategy to sensitize proliferating lymphoma cells to PI3K inhibition.
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                Author and article information

                Contributors
                dssgeneral@163.com
                czxy12@163.com
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                16 February 2018
                March 2018
                : 109
                : 3 , Thematic section: Cancer Genomics and Immunology ( doiID: 10.1111/cas.2018.109.issue-3 )
                : 656-665
                Affiliations
                [ 1 ] Department of Human Anatomy and Sichuan Key Laboratory of Medical Imaging North Sichuan Medical College Nanchong China
                [ 2 ] School of Life Sciences Chongqing University Chongqing China
                [ 3 ] Department of Pathology Affiliated Hospital of North Sichuan Medical College Nanchong China
                [ 4 ] Sichuan Key Laboratory of Medical Imaging and Department of Radiology Affiliated Hospital of North Sichuan Medical College Nanchong China
                Author notes
                [*] [* ] Correspondence

                Xiaoming Zhang, Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.

                Email: czxy12@ 123456163.com

                or

                Shishan Deng, Department of Human Anatomy, Premedical College, North Sichuan Medical College, Nanchong, China.

                Email: dssgeneral@ 123456163.com

                Author information
                http://orcid.org/0000-0001-5338-7825
                Article
                CAS13495
                10.1111/cas.13495
                5834791
                29288563
                65684c18-3faf-46b6-a22d-cc54fa49d043
                © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 19 September 2017
                : 12 December 2017
                : 20 December 2017
                Page count
                Figures: 7, Tables: 0, Pages: 10, Words: 5668
                Funding
                Funded by: Local University Development Foundation of China
                Award ID: SCKBMI‐13‐003
                Categories
                Original Article
                Original Articles
                Carcinogenesis
                Custom metadata
                2.0
                cas13495
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:03.03.2018

                Oncology & Radiotherapy
                cdc37,cdk4,cell survival,colorectal carcinoma,p‐rb1
                Oncology & Radiotherapy
                cdc37, cdk4, cell survival, colorectal carcinoma, p‐rb1

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