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      Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation

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          Abstract

          Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. Dasatinib dramatically decreased 5-Fu triggered apoptosis in colon carcinoma via suppression of Src activation. Our findings may have partially explained why dasatinib combined with FOLFOX failed to show a meaningful clinical response in mCRC.

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          A renaissance for SRC.

          Timothy Yeatman (2004)
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            Src family kinases in tumor progression and metastasis.

            Justin Summy, Gary Gallick (2003)
            The Src family of non-receptor protein tyrosine kinases plays critical roles in a variety of cellular signal transduction pathways, regulating such diverse processes as cell division, motility, adhesion, angiogenesis, and survival. Constitutively activated variants of Src family kinases, including the viral oncoproteins v-Src and v-Yes, are capable of inducing malignant transformation of a variety of cell types. Src family kinases, most notably although not exclusively c-Src, are frequently overexpressed and/or aberrantly activated in a variety of epithelial and non-epithelial cancers. Activation is very common in colorectal and breast cancers, and somewhat less frequent in melanomas, ovarian cancer, gastric cancer, head and neck cancers, pancreatic cancer, lung cancer, brain cancers, and blood cancers. Further, the extent of increased Src family activity often correlates with malignant potential and patient survival. Activation of Src family kinases in human cancers may occur through a variety of mechanisms and is frequently a critical event in tumor progression. Exactly how Src family kinases contribute to individual tumors remains to be defined completely, however they appear to be important for multiple aspects of tumor progression, including proliferation, disruption of cell/cell contacts, migration, invasiveness, resistance to apoptosis, and angiogenesis. This review details the evidence for Src family activation in human tumors, and emphasizes possible consequences to tumor progression. Given the ability of Src and its family members to participate in so many aspects of tumor progression and metastasis, Src family kinases are attractive targets for future anti-cancer therapeutics.
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              The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome.

              Maximilian Würstle, Maike A Laussmann, Markus Rehm (2012)
              Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in apoptosis signal transduction, the initiator caspases-2, -8 and -9 are activated at multi-protein activation platforms, and activation is thought to involve homo-dimerisation of the monomeric zymogens. Caspase-9, the essential initiator caspase required for apoptosis signalling through the mitochondrial pathway, is activated on the apoptosome complex, and failure to activate caspase-9 has profound pathophysiological consequences. Here, we review the pertinent literature on which the currently prevalent understanding of caspase-9 activation is based, extend this view by insight obtained from recent structural and kinetic studies on caspase-9 signalling, and describe an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This integrated view allows us to postulate and to discuss functional consequences for caspase-9 activation and apoptosis execution that may take centre stage in future experimental cell research on apoptosis signalling. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Yang Fu: +86-13733873215 , fuyang@zzu.edu.cn
                Feng Zhu: +86-18971681230 , fengzhu@hust.edu.cn
                Journal
                Journal ID (nlm-ta): Cell Death Discov
                Journal ID (iso-abbrev): Cell Death Discov
                Title: Cell Death Discovery
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2058-7716
                Publication date (Electronic): 23 May 2018
                Publication date PMC-release: 23 May 2018
                Publication date Collection: 2018
                Volume: 4
                Electronic Location Identifier: 61
                Affiliations
                [1 ]GRID grid.412633.1, Department of General Surgery, , The First Affiliated Hospital of Zhengzhou University, ; 450052 Zhengzhou, China
                [2 ]GRID grid.412633.1, Department of Ophthalmology, , The First Affiliated Hospital of Zhengzhou University, ; 450052 Zhengzhou, China
                [3 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Biochemistry and Molecular Biology, School of Basic Medicine, , Huazhong University of Science and Technology, ; 430030 Wuhan, Hubei PR China
                [4 ]GRID grid.488200.6, Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, , Chongqing Population and Family Planning Science and Technology Research Institute, ; 400020 Chongqing, China
                [5 ]GRID grid.412719.8, Department of Obstetrics and Gynecology, , The Third Affiliated Hospital of Zhengzhou University, ; 450052 Zhengzhou, China
                [6 ]GRID grid.440320.1, Department of General Surgery, , Xinyang Central Hospital, ; 464000 Xinyang, China
                [7 ]GRID grid.412633.1, Department of Oncology, , The First Affiliated Hospital of Zhengzhou University, ; 450052 Zhengzhou, China
                Article
                Publisher ID: 62
                DOI: 10.1038/s41420-018-0062-5
                PMC ID: 5966379
                SO-VID: 5ad819dd-2927-4fe0-9ac9-0786d569cdf3
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 2 March 2018
                Date revision received : 9 April 2018
                Date accepted : 1 May 2018
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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