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1
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Raji L, Tetteh A, Amin ARMR. Role of c-Src in Carcinogenesis and Drug Resistance. Cancers (Basel) 2023; 16:32. [PMID: 38201459 PMCID: PMC10778207 DOI: 10.3390/cancers16010032] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The aberrant transformation of normal cells into cancer cells, known as carcinogenesis, is a complex process involving numerous genetic and molecular alterations in response to innate and environmental stimuli. The Src family kinases (SFK) are key components of signaling pathways implicated in carcinogenesis, with c-Src and its oncogenic counterpart v-Src often playing a significant role. The discovery of c-Src represents a compelling narrative highlighting groundbreaking discoveries and valuable insights into the molecular mechanisms underlying carcinogenesis. Upon oncogenic activation, c-Src activates multiple downstream signaling pathways, including the PI3K-AKT pathway, the Ras-MAPK pathway, the JAK-STAT3 pathway, and the FAK/Paxillin pathway, which are important for cell proliferation, survival, migration, invasion, metastasis, and drug resistance. In this review, we delve into the discovery of c-Src and v-Src, the structure of c-Src, and the molecular mechanisms that activate c-Src. We also focus on the various signaling pathways that c-Src employs to promote oncogenesis and resistance to chemotherapy drugs as well as molecularly targeted agents.
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Affiliation(s)
| | | | - A. R. M. Ruhul Amin
- Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV 25755, USA; (L.R.); (A.T.)
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2
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Phosphorylation-mediated interaction between human E26 transcription factor 1 and specific protein 1 is required for tumor cell migration. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1441-1452. [PMID: 36305724 PMCID: PMC9828152 DOI: 10.3724/abbs.2022148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Transcription factors, human E26 transcription factor 1 (Ets1) and specific protein 1 (Sp1), are known to induce gene expression in tumorigenicity. High Ets1 expression is often associated with colorectal tumorigenesis. In this study, we discover that metastasis and clone formation in SW480 cells mainly depend on the direct interaction between Ets1 and Sp1 instead of high Ets1 expression. The interaction domains are further addressed to be the segment at Sp1(626-708) and the segment at Ets1(244-331). In addition, the phosphorylation inhibition of Ets1 at Tyr283 by either downregulation of Src kinase or Src family inhibitor treatment decreases the interaction between Sp1 and Ets1 and suppresses SW480 migration. Either administration or overexpression of the peptides harboring the interaction segment strongly inhibits the colony formation and migration of SW480 cells. Our findings suggest that the interaction between Ets1 and Sp1 rather than Ets1 alone promotes transformation in SW480 cells and provide new insight into the Ets1 and Sp1 interaction as an antitumour target in SW480 cells.
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3
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Ebadi Zavieh S, Safari F. The Antitumor Activity of hAMSCs Secretome in HT-29 Colon Cancer Cells Through Downregulation of EGFR/c-Src/IRTKS Expression and p38/ERK1/2 Phosphorylation. Cell Biochem Biophys 2022; 80:395-402. [PMID: 35150389 DOI: 10.1007/s12013-022-01066-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2022] [Indexed: 11/03/2022]
Abstract
Colon cancer is considered as one of the main causes of mortality worldwide. Identifying a novel and more effective platform with fewer side effects is still progress. In various cancer types, Epidermal growth factor receptor (EGFR) and c-Src (a key mediator in EGFR signaling pathway) are the key targets for cancer therapy. Moreover, insulin receptor tyrosine kinase substrate (IRTKS or BAI1-associated protein 2-like 1: BAIAP2L1) is a member of the subfamily of inverse BAR (I-BAR) domain proteins, which mediates cell morphology and movement through regulation of actin polymerization. In this study, we employed a co-culture system using Transwell six-well plates. After 72 h, hAMSCs-treated HT-29 cells, EGFR, c-Src, IRTKS, p38, and ERK1/2 expression were analyzed using quantitative real time PCR (qRT-PCR) and western blot methods. The significant reduction in tumor cell growth and motility through downregulation of EGFR/c-Src/IRTKS expression and p38/ERK1/2 phosphorylation in HT-29 cells was demonstrated based on 2D and 3D cell culture models. The induction of cellular apoptosis was also found. Our results support the idea that the hAMSCS secretome has therapeutic effects on cancer cells. However, further experiments will be required to identify the exact molecular mechanisms.
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Affiliation(s)
- Shamin Ebadi Zavieh
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
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4
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Jin W. Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications. Cancers (Basel) 2020; 12:cancers12051339. [PMID: 32456226 PMCID: PMC7281431 DOI: 10.3390/cancers12051339] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 12/11/2022] Open
Abstract
Src family kinases (SFKs) are non-receptor kinases that play a critical role in the pathogenesis of colorectal cancer (CRC). The expression and activity of SFKs are upregulated in patients with CRC. Activation of SFKs promotes CRC cell proliferation, metastases to other organs and chemoresistance, as well as the formation of cancer stem cells (CSCs). The enhanced expression level of Src is associated with decreased survival in patients with CRC. Src-mediated regulation of CRC progression involves various membrane receptors, modulators, and suppressors, which regulate Src activation and its downstream targets through various mechanisms. This review provides an overview of the current understanding of the correlations between Src and CRC progression, with a special focus on cancer cell proliferation, invasion, metastasis and chemoresistance, and formation of CSCs. Additionally, this review discusses preclinical and clinical strategies to improve the therapeutic efficacy of drugs targeting Src for treating patients with CRC.
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Affiliation(s)
- Wook Jin
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-840, Korea
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5
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Shimada Y, Muneoka Y, Nagahashi M, Ichikawa H, Tajima Y, Hirose Y, Ando T, Nakano M, Sakata J, Kameyama H, Takii Y, Ling Y, Okuda S, Takabe K, Wakai T. BRAF V600E and SRC mutations as molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer. Sci Rep 2019; 9:2466. [PMID: 30792536 PMCID: PMC6384937 DOI: 10.1038/s41598-019-39328-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 01/22/2019] [Indexed: 12/23/2022] Open
Abstract
Comprehensive genomic sequencing (CGS) enables us to detect numerous genetic alterations in a single assay. We aimed to identify molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer (CRC) using CGS. One-hundred eleven patients with Stage IV CRC who underwent primary tumor resection were analyzed. We retrospectively investigated genetic alterations using CGS of a 415-gene panel. Clinicopathological variables and genetic alterations were analyzed to identify independent prognostic factors of overall survival (OS). Forty-five of 111 patients had R0 resection; of these, 11 patients underwent conversion surgery. Univariate and multivariate analyses identified histopathological grade 3, R0 resection, BRAF V600E mutation, and SRC mutation as independent prognostic factors for OS (P = 0.041, P = 0.013, P = 0.005, and P = 0.023, respectively). BRAF V600E and SRC mutations were mutually exclusive, and SRC mutation was significantly associated with left-sided tumor and liver metastasis compared to BRAF V600E mutation (P = 0.016 and P = 0.025, respectively). Eleven of the 74 initially unresectable patients underwent conversion surgery for R0 resection, yet none harbored BRAF V600E or SRC mutations. BRAF V600E and SRC mutations are important molecular markers which can predict prognosis and conversion surgery in Stage IV CRC.
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Affiliation(s)
- Yoshifumi Shimada
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Yusuke Muneoka
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroshi Ichikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yosuke Tajima
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Hirose
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takuya Ando
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masato Nakano
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hitoshi Kameyama
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yasumasa Takii
- Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Yiwei Ling
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shujiro Okuda
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuaki Takabe
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Breast Surgery, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
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6
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Perez M, Lucena-Cacace A, Marín-Gómez LM, Padillo-Ruiz J, Robles-Frias MJ, Saez C, Garcia-Carbonero R, Carnero A. Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src. Oncotarget 2018; 7:33111-24. [PMID: 27105527 PMCID: PMC5078079 DOI: 10.18632/oncotarget.8880] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/31/2016] [Indexed: 01/26/2023] Open
Abstract
Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activated Src kinase, measured as phospho-Src at the Tyr419 residue in CRC cell lines, can promote colorectal carcinoma cell resistance to oxaliplatin, but not to 5-fluorouracil (5FU), and that inhibition of this protein restores sensitivity to oxaliplatin. Similar results were observed with in vivo patient-derived xenograft (PDX) models that were orthotopically grown in murine livers. In PDX tumor lines derived from human CRC liver metastasis, dasatinib, a Src inhibitor, increases sensitivity to oxaliplatin only in tumors with high p-Src. However, dasatinib did not modify sensitivity to 5FU in any of the models. Our data suggest that chemoresistance induced by p-Src is specific to oxaliplatin, and that p-Src levels can be used to identify patients who may benefit from this combination therapy. These results are relevant for clinicians as they identify a novel biomarker of drug resistance that is suitable to pharmacological manipulation.
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Affiliation(s)
- Marco Perez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Antonio Lucena-Cacace
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Luis Miguel Marín-Gómez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.,Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain
| | - Javier Padillo-Ruiz
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.,Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain
| | - Maria Jose Robles-Frias
- Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain.,Present address: HUVR-IBiS Biobank, Virgen del Rocío University Hospital, Seville, Spain
| | - Carmen Saez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.,Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain
| | - Rocio Garcia-Carbonero
- Department of Medical Oncology, Virgen del Rocío University Hospital, Seville, Spain.,Present address: Department of Medical Oncology, 12 of October University Hospital, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
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7
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Ke L, Xiang Y, Guo X, Lu J, Xia W, Yu Y, Peng Y, Wang L, Wang G, Ye Y, Yang J, Liang H, Kang T, Lv X. c-Src activation promotes nasopharyngeal carcinoma metastasis by inducing the epithelial-mesenchymal transition via PI3K/Akt signaling pathway: a new and promising target for NPC. Oncotarget 2017; 7:28340-55. [PMID: 27078847 PMCID: PMC5053730 DOI: 10.18632/oncotarget.8634] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 03/18/2016] [Indexed: 01/21/2023] Open
Abstract
Aberrant activation of cellular Src (c-Src), a non-receptor tyrosine kinase, could promote cancer progression through activating its downstream signaling pathways. However, the roles of c-Src and phosphorylated-Src (p-Src) in nasopharyngeal carcinoma (NPC) progression are rarely investigated. Herein, we have identified high c-Src concentrations in the serum of NPC patients with distant metastasis using high-throughput protein microarrays. Levels of c-Src in serum and p-Src in human primary NPC samples were unfavorable independent prognostic factors for cancer-specific survival, disease-free survival, and distant metastasis-free survival. Depletion or inactivation of c-Src in NPC cells using sgRNA with CRISPR/Cas9 system or PP2 decreased cell viability, colony formation, migration and invasion in vitro and metastasis in vivo. In contrast, these malignancies could be up-regulated by overexpressed c-Src in a NPC cell line with low-metastasis potential. Furthermore, p-Src was involved in promoting NPC cell metastasis by inducing the epithelial-mesenchymal transition (EMT) process via activating the PI3K/Akt pathway and cytoskeleton remodeling. The p-Src-induced EMT process could be retarded by PP2, which mediated by down-regulating the PI3K/Akt pathway. In conclusion, elevated levels of c-Src in serum and p-Src in primary NPC tissue correlated with poor outcomes of NPC patients. And aberrant activation of c-Src facilitated NPC cells with malignant potential, especially metastasis ability, which mediated by the PI3K/Akt pathway activation and sequentially induced the EMT process. These findings unveiled a promising approach for targeted therapy of advanced NPC.
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Affiliation(s)
- Liangru Ke
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yanqun Xiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiang Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jinping Lu
- Medical Research Center and Clinical Laboratory, Zhuhai Hospital, Jinan University, Zhuhai People's Hospital, Zhuhai, China
| | - Weixiong Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yahui Yu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yongjian Peng
- Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Li Wang
- Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Gang Wang
- Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yanfang Ye
- Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Jing Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hu Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tiebang Kang
- Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xing Lv
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China
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8
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Advani G, Lim YC, Catimel B, Lio DSS, Ng NLY, Chüeh AC, Tran M, Anasir MI, Verkade H, Zhu HJ, Turk BE, Smithgall TE, Ang CS, Griffin M, Cheng HC. Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine. Cell Commun Signal 2017; 15:29. [PMID: 28784162 PMCID: PMC5547543 DOI: 10.1186/s12964-017-0186-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 07/28/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND C-terminal Src kinase (Csk) and Csk-homologous kinase (Chk) are the major endogenous inhibitors of Src-family kinases (SFKs). They employ two mechanisms to inhibit SFKs. First, they phosphorylate the C-terminal tail tyrosine which stabilizes SFKs in a closed inactive conformation by engaging the SH2 domain in cis. Second, they employ a non-catalytic inhibitory mechanism involving direct binding of Csk and Chk to the active forms of SFKs that is independent of phosphorylation of their C-terminal tail. Csk and Chk are co-expressed in many cell types. Contributions of the two mechanisms towards the inhibitory activity of Csk and Chk are not fully clear. Furthermore, the determinants in Csk and Chk governing their inhibition of SFKs by the non-catalytic inhibitory mechanism are yet to be defined. METHODS We determined the contributions of the two mechanisms towards the inhibitory activity of Csk and Chk both in vitro and in transduced colorectal cancer cells. Specifically, we assayed the catalytic activities of Csk and Chk in phosphorylating a specific peptide substrate and a recombinant SFK member Src. We employed surface plasmon resonance spectroscopy to measure the kinetic parameters of binding of Csk, Chk and their mutants to a constitutively active mutant of the SFK member Hck. Finally, we determined the effects of expression of recombinant Chk on anchorage-independent growth and SFK catalytic activity in Chk-deficient colorectal cancer cells. RESULTS Our results revealed Csk as a robust enzyme catalysing phosphorylation of the C-terminal tail tyrosine of SFKs but a weak non-catalytic inhibitor of SFKs. In contrast, Chk is a poor catalyst of SFK tail phosphorylation but binds SFKs with high affinity, enabling it to efficiently inhibit SFKs with the non-catalytic inhibitory mechanism both in vitro and in transduced colorectal cancer cells. Further analyses mapped some of the determinants governing this non-catalytic inhibitory mechanism of Chk to its kinase domain. CONCLUSIONS SFKs are activated by different upstream signals to adopt multiple active conformations in cells. SFKs adopting these conformations can effectively be constrained by the two complementary inhibitory mechanisms of Csk and Chk. Furthermore, the lack of this non-catalytic inhibitory mechanism accounts for SFK overactivation in the Chk-deficient colorectal cancer cells.
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Affiliation(s)
- Gahana Advani
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
- Cell Signalling Research Laboratories, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010 Australia
| | - Ya Chee Lim
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong, Brunei Darussalam
| | - Bruno Catimel
- Walter and Eliza Hall Institute for Medical Research and Department of Medical Biology, University of Melbourne, Parkville, VIC 3010 Australia
| | - Daisy Sio Seng Lio
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
- Cell Signalling Research Laboratories, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010 Australia
| | - Nadia L. Y. Ng
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
- Cell Signalling Research Laboratories, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010 Australia
| | - Anderly C. Chüeh
- Walter and Eliza Hall Institute for Medical Research and Department of Medical Biology, University of Melbourne, Parkville, VIC 3010 Australia
| | - Mai Tran
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
| | - Mohd Ishtiaq Anasir
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
| | - Heather Verkade
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
| | - Hong-Jian Zhu
- Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3052 Australia
| | - Benjamin E. Turk
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT USA
| | - Thomas E. Smithgall
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Ching-Seng Ang
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
| | - Michael Griffin
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
| | - Heung-Chin Cheng
- Department of Biochemistry & Molecular Biology, University of Melbourne, Parkville, VIC 3010 Australia
- Bio21 Biotechnology and Molecular Science Institute, University of Melbourne, Parkville, VIC 3010 Australia
- Cell Signalling Research Laboratories, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010 Australia
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9
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Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells. Nat Commun 2017; 8:15237. [PMID: 28508872 PMCID: PMC5440822 DOI: 10.1038/ncomms15237] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 03/10/2017] [Indexed: 12/25/2022] Open
Abstract
Studies of the role of actin in tumour progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fibre-mediated cell stiffening could drive tumour growth during premalignant stages. A careful consideration of the mechanical properties of tumour cells could therefore offer new avenues of exploration when designing cancer-targeting therapies. When cells acquire a malignant phenotype they become less stiff and this helps migration and invasion favouring metastasis. Here the authors show that Src-driven cell transformation and transition to a less stiff state follows an event of membrane stiffening due to stress fibres accumulation.
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10
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Parseghian CM, Parikh NU, Wu JY, Jiang ZQ, Henderson L, Tian F, Pastor B, Ychou M, Raghav K, Dasari A, Fogelman DR, Katsiampoura AD, Menter DG, Wolff RA, Eng C, Overman MJ, Thierry AR, Gallick GE, Kopetz S. Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer. Clin Cancer Res 2017; 23:4146-4154. [PMID: 28280091 DOI: 10.1158/1078-0432.ccr-16-3138] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/10/2017] [Accepted: 03/07/2017] [Indexed: 12/28/2022]
Abstract
Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab.Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort.Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies.Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146-54. ©2017 AACR.
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Affiliation(s)
- Christine M Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Nila U Parikh
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ji Yuan Wu
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhi-Qin Jiang
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Laura Henderson
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Feng Tian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Brice Pastor
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
| | - Marc Ychou
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David R Fogelman
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anastasia D Katsiampoura
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alain R Thierry
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
| | - Gary E Gallick
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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11
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Kawczyk-Krupka A, Sieroń-Stołtny K, Latos W, Czuba Z, Kwiatek B, Potempa M, Wasilewska K, Król W, Stanek A. ALA-induced photodynamic effect on vitality, apoptosis, and secretion of vascular endothelial growth factor (VEGF) by colon cancer cells in normoxic environment in vitro. Photodiagnosis Photodyn Ther 2016; 13:308-315. [DOI: 10.1016/j.pdpdt.2015.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 08/24/2015] [Accepted: 09/08/2015] [Indexed: 12/27/2022]
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12
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Cordero JB, Ridgway RA, Valeri N, Nixon C, Frame MC, Muller WJ, Vidal M, Sansom OJ. c-Src drives intestinal regeneration and transformation. EMBO J 2014; 33:1474-91. [PMID: 24788409 PMCID: PMC4194090 DOI: 10.1002/embj.201387454] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 03/11/2014] [Accepted: 04/08/2014] [Indexed: 12/11/2022] Open
Abstract
The non-receptor tyrosine kinase c-Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult Drosophila and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage-induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self-renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non-redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation in vivo.
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Affiliation(s)
- Julia B Cordero
- The Beatson Institute for Cancer Research, Bearsden Glasgow, UK
| | | | | | - Colin Nixon
- The Beatson Institute for Cancer Research, Bearsden Glasgow, UK
| | - Margaret C Frame
- Edinburgh Cancer Research Centre Institute of Genetics & Molecular Medicine University of Edinburgh, Edinburgh, UK
| | - William J Muller
- Goodman Cancer Research Center McGill University, Montreal, QC, Canada
| | - Marcos Vidal
- The Beatson Institute for Cancer Research, Bearsden Glasgow, UK
| | - Owen J Sansom
- The Beatson Institute for Cancer Research, Bearsden Glasgow, UK
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13
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Gargalionis AN, Karamouzis MV, Papavassiliou AG. The molecular rationale of Src inhibition in colorectal carcinomas. Int J Cancer 2014; 134:2019-2029. [PMID: 23733480 DOI: 10.1002/ijc.28299] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
Src has been one of the most studied proto‐oncogenes. The cellular Src (c‐Src) holds a critical role in several human malignancies and has emerged as a key factor that promotes tumor progression during the multistep process of colorectal cancer (CRC) pathogenesis. The robust activation of Src in CRC of aggressive phenotype and poor prognosis seems to be a subsequent event of a strong link between its deregulated activity and the tumor's cell adhesion properties, invasiveness and metastatic potential. The rarely detected genetic defects drive interest in signaling networks that control Src kinase activity and integrate the association of Src with receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). Therefore, a dynamic crosstalk is being formed with oncogenic capacity and therapeutic applications, because Src inhibition seems to sensitize previously unresponsive cancer cells to chemotherapy and anti‐EGFR inhibitors. The present review explores the molecular basis behind Src inhibition in colorectal carcinomas. Furthermore, preclinical studies and clinical trials of Src inhibitors and combination regimens are discussed, providing new insights for further investigation and new therapeutic strategies.
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Affiliation(s)
- Antonios N. Gargalionis
- Molecular Oncology Unit Department of Biological Chemistry, University of Athens Medical School Athens Greece
| | - Michalis V. Karamouzis
- Molecular Oncology Unit Department of Biological Chemistry, University of Athens Medical School Athens Greece
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit Department of Biological Chemistry, University of Athens Medical School Athens Greece
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14
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Strickler JH, McCall S, Nixon AB, Brady JC, Pang H, Rushing C, Cohn A, Starodub A, Arrowood C, Haley S, Meadows KL, Morse MA, Uronis HE, Blobe GC, Hsu SD, Zafar SY, Hurwitz HI. Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer. Invest New Drugs 2014; 32:330-9. [PMID: 24173967 PMCID: PMC4108590 DOI: 10.1007/s10637-013-0042-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 10/16/2013] [Indexed: 01/07/2023]
Abstract
PURPOSE Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). METHODS Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). RESULTS Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). CONCLUSIONS The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.
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Affiliation(s)
| | | | | | - John C. Brady
- Duke University Medical Center, Durham, NC, 27710, USA
| | - Herbert Pang
- Duke University Medical Center, Durham, NC, 27710, USA
| | | | - Allen Cohn
- Rocky Mountain Cancer Centers Denver, CO, 80218, USA
| | - Alexander Starodub
- Duke University Medical Center, Durham, NC, 27710, USA
- Indiana University Health Goshen Cancer Center, Goshen, IN, 46526, USA
| | | | - Sherri Haley
- Duke University Medical Center, Durham, NC, 27710, USA
| | | | | | | | | | - S. David Hsu
- Duke University Medical Center, Durham, NC, 27710, USA
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15
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Chen J, Elfiky A, Han M, Chen C, Saif MW. The Role of Src in Colon Cancer and Its Therapeutic Implications. Clin Colorectal Cancer 2014; 13:5-13. [DOI: 10.1016/j.clcc.2013.10.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 10/02/2013] [Indexed: 12/13/2022]
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16
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Rotert JV, Leupold J, Hohenberger P, Nowak K, Allgayer H. Src activity is increased in gastrointestinal stromal tumors--analysis of associations with clinical and other molecular tumor characteristics. J Surg Oncol 2014; 109:597-605. [PMID: 24391050 DOI: 10.1002/jso.23544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 11/30/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND Increased activity of Src has been found in several human cancers, and often is associated with poor clinical outcome. The present study aimed to determine whether Src activity is increased in gastrointestinal stromal tumors (GIST), and whether it correlates with established tumor or patient characteristics and prognosis. METHODS Tumor/normal tissues of 29 patients were analyzed for Src activity/protein with kinase assays, and for VEGF/VEGFR with immunohistochemical staining. RESULTS Src activity was higher in tumor than in normal tissues (P = 0.093). However, when imatinib responders were excluded from the analyses, it was significantly higher in the tumor tissue (P = 0.017). Additionally, it was higher in primary compared to recurrent tumors or metastasis (P = 0.04). Univariate survival analysis showed a longer overall survival for patients with high Src activity (P = 0.038). In multivariate analysis, the response to imatinib treatment was the only survival-influencing factor (P = 0.072). CONCLUSIONS Src activity is increased in GIST. In contrast to most other tumor entities, it does not correlate with poor clinical outcome, but decreases during the progression from primary tumor to recurrence and metastasis, especially under therapy with imatinib. Additionally, our results show that higher Src activity is associated with longer overall survival.
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Affiliation(s)
- Julia Valerie Rotert
- Department of Surgery, Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
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17
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Shi M, Lou B, Ji J, Shi H, Zhou C, Yu Y, Liu B, Zhu Z, Zhang J. Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells. Cancer Chemother Pharmacol 2013; 72:35-44. [PMID: 23712327 DOI: 10.1007/s00280-013-2166-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 04/12/2013] [Indexed: 01/13/2023]
Abstract
PURPOSE The aim of this study is to investigate whether dasatinib, a Src inhibitor, has the synergistic effect with oxaliplatin in treating gastric cancer cells. METHODS The baseline levels of total Src and p-Src in 10 human gastric cancer cell lines and gastric mucosa epithelial cell line GES-1 were detected by Western blot (WB). The changes of Src and p-Src expression after oxaliplatin exposure were evaluated by WB. The combination indices and clonogenic assay were used to evaluate the synergistic effects of dasatinib with oxaliplatin on cell growth and proliferation in vitro. Gastric cancer xenografts in nude mice were established and treated by oxaliplatin with or without dasatinib. The tumor growth curves were calculated and the impacts of different treatment on the tumor proliferation and src protein expression in gastric cancer xenografts were determined by immunohistochemistry staining and WB. RESULTS The different levels of Src expression in gastric cancer cells were related with their different sensitivity to oxaliplatin. The expression of p-Src, but not total Src, was elevated after oxaliplatin exposure both in vitro and in vivo. Dasatinib could dramatically inhibit p-Src expression, and combination indices demonstrated that dasatinib and oxaliplatin were synergistic in inhibiting gastric cancer cell growth. Dasatinib plus oxaliplatin were more effective in inhibiting clone formation than oxaliplatin or dasatinib monotherapy in clonogenic assay. The tumor volume and tumor weight of xenografts were significantly lower in doublet treatment group than those in single-agent treatment groups. CONCLUSIONS Dasatinib plays synergistic role with oxaliplatin in inhibiting gastric cancer cell growth both in vitro and in vivo, via inhibiting Src activity stimulated by oxaliplatin.
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Affiliation(s)
- Min Shi
- Department of Surgery, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, People's Republic of China
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18
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Fiordalisi JJ, Dewar BJ, Graves LM, Madigan JP, Cox AD. Src-mediated phosphorylation of the tyrosine phosphatase PRL-3 is required for PRL-3 promotion of Rho activation, motility and invasion. PLoS One 2013; 8:e64309. [PMID: 23691193 PMCID: PMC3656837 DOI: 10.1371/journal.pone.0064309] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 04/11/2013] [Indexed: 01/13/2023] Open
Abstract
The metastasis-associated tyrosine phosphatase PRL-3/PTP4A is upregulated in numerous cancers, but the mechanisms modulating PRL-3 activity other than its expression levels have not been investigated. Here we report evidence for both Src-dependent tyrosine phosphorylation of PRL-3 and Src-mediated regulation of PRL-3 biological activities. We used structural mutants, pharmacological inhibitors and siRNA to demonstrate Src-dependent phosphorylation of endogenous PRL-3 in SW480 colon cancer cells. We also demonstrated that PRL-3 was not tyrosine phosphorylated in SYF mouse embryo fibroblasts deficient in Src, Yes and Fyn unless Src was re-expressed. Further, we show that platelet-derived growth factor (PDGF) can stimulate PRL-3 phosphorylation in a Src-dependent manner. Finally, we show that PRL-3-induced cell motility, Matrigel invasion and activation of the cytoskeleton-regulating small GTPase RhoC were abrogated in the presence of the phosphodeficient PRL-3 mutant Y53F, or by use of a Src inhibitor. Thus, PRL-3 requires the activity of a Src kinase, likely Src itself, to promote these cancer-associated phenotypes. Our data establish a model for the regulation of PRL-3 by Src that supports the possibility of their coordinate roles in signaling pathways promoting invasion and metastasis, and supports simultaneous use of novel molecularly targeted therapeutics directed at these proteins.
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Affiliation(s)
- James J. Fiordalisi
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Brian J. Dewar
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Lee M. Graves
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - James P. Madigan
- Curriculum in Genetics & Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Adrienne D. Cox
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Curriculum in Genetics & Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
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19
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Nourazarian AR, Pashaei-Asl R, Omidi Y, Najar AG. c-Src antisense complexed with PAMAM denderimes decreases of c-Src expression and EGFR-dependent downstream genes in the human HT-29 colon cancer cell line. Asian Pac J Cancer Prev 2013; 13:2235-40. [PMID: 22901200 DOI: 10.7314/apjcp.2012.13.5.2235] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
c-Src is one member of non-receptor tyrosine kinase protein family that has over expression and activation in many human cancer cells. It has been shown that c-Src is implicated in various downstream signaling pathways associated with EGFR-dependent signaling such as MAPK and STAT5 pathways. Transactivation of EGFR by c-Src is more effective than EGFR ligands. To inhibit the c-Src expression, we used c-Src antisense oligonucleotide complexed with PAMAM Denderimes. The effect of c-Src antisense oligonucleotide on HT29 cell proliferation was determined by MTT assay. Then, the expression of c-Src, EGFR and the genes related to EGFR-depended signaling with P53 was applied by real time PCR. We used western blot analysis to elucidate the effect of antisense on the level of c-Src protein expression. The results showed, c-Src antisense complexed with PAMAM denderimers has an effective role in decrease of c-Src expression and EGFR-dependent downstream genes.
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Affiliation(s)
- Ali Reza Nourazarian
- Department of Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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20
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Src tyrosine kinase inhibitors in the treatment of lung cancer: rationale and clinical data. ACTA ACUST UNITED AC 2012. [DOI: 10.4155/cli.12.27] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer. Proc Natl Acad Sci U S A 2012; 109:2302-7. [PMID: 22308320 DOI: 10.1073/pnas.1106799109] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.
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22
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Kumar S, Singh B, Dimmock JR, Sharma RK. N-myristoyltransferase in the leukocytic development processes. Cell Tissue Res 2011; 345:203-11. [PMID: 21698528 PMCID: PMC3327710 DOI: 10.1007/s00441-011-1202-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 06/03/2011] [Indexed: 02/07/2023]
Abstract
The lipidic modification of proteins has recently been shown to be of immense importance, although many of the roles of these modifications remain as yet unidentified. One of such key modifications occurring on several proteins is the covalent addition of a 14-carbon long saturated fatty acid, a process termed myristoylation. Myristoylation can occur during both co-translational protein synthesis and posttranslationally, confers lipophilicity to protein molecules, and controls protein functions. The protein myristoylation process is catalyzed by the enzyme N-myristoyltransferase (NMT), which exists as two isoforms: NMT1 and NMT2. NMT1 is essential for growth and development, during which rapid cellular proliferation is required, in a variety of organisms. NMT1 is also reported to be elevated in many cancerous states, which also involve rapid cellular growth, albeit in an unwanted and uncontrolled manner. The delineation of myristoylation-dependent cellular functions is still in a state of infancy, and many of the roles of the myristoylated proteins remain to be established. The development of cells of the leukocytic lineage represents a phase of rapid growth and development, and we have observed that NMT1 plays a role in this process. The current review outlines the roles of NMT1 in the growth and differentiation of the cells of leukocytic origin. The described studies clearly demonstrate the roles of NMT1 in the regulation of the developmental processes of the leukocytes cells and provide a basis for further research with the aim of unraveling the roles of protein myristoylation in both cellular and physiological context.
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Affiliation(s)
- Sujeet Kumar
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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23
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Nautiyal J, Kanwar SS, Yu Y, Majumdar AP. Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal 2011; 6:7. [PMID: 21774804 PMCID: PMC3162943 DOI: 10.1186/1750-2187-6-7] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2011] [Accepted: 07/20/2011] [Indexed: 02/06/2023] Open
Abstract
Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary agent with pleiotropic effect) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs sub-population. Remnants of spontaneous adenomas from APCMin +/- mice treated with dasatinib and/or curcumin were analyzed for several cancer stem cell markers (ALDH, CD44, CD133 and CD166). Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant (referred to as CR) cells. The effectiveness of the combination therapy in inhibiting growth, invasive potential and stemness was examined in colon cancer CR cells. The residual tumors from APCMin +/- mice treated with dasatinib and/or curcumin showed 80-90% decrease in the expression of the CSC markers ALDH, CD44, CD133, CD166. The colon cancer CR cells showed a higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR HCT-116 and CR HT-29 cells, as determined by Calcusyn analysis. The combinatorial therapy inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. Our data suggest that the combination therapy of dasatinib and curcumin may be a therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.
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Affiliation(s)
- Jyoti Nautiyal
- Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA.
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24
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Brady RRW, Loveridge CJ, Dunlop MG, Stark LA. c-Src dependency of NSAID-induced effects on NF-κB-mediated apoptosis in colorectal cancer cells. Carcinogenesis 2011; 32:1069-77. [PMID: 21551129 DOI: 10.1093/carcin/bgr077] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Long-term aspirin or related non-steroidal anti-inflammatory drugs (NSAIDs) ingestion can protect against colorectal cancer (CRC). NSAIDs have a pro-apoptotic activity and we have shown that stimulation of the nuclear factor-kappaB (NF-κB) pathway is a key component of this pro-apoptotic effect. However, the upstream pathways have yet to be fully elucidated. Here, we demonstrate that aspirin activates the c-Src tyrosine kinase pathway in CRC cells. We show that c-Src activation occurs in a time- and dose-dependent manner, preceding aspirin-mediated degradation of IκBα, nuclear/nucleolar translocation of NF-κB/RelA and induction of apoptosis. Furthermore, inhibition of c-Src activity, by chemical inhibition or expression of a kinase dead form of the protein abrogates aspirin-mediated degradation of IκBα, nuclear translocation of RelA and apoptosis, suggesting a causal link. Expression of constitutively active c-Src mimics aspirin-induced stimulation of the NF-κB pathway. The NSAIDs sulindac, sulindac sulphone and indomethacin all similarly activate a c-Src-dependent NF-κB and apoptotic response. These data provide compelling evidence that c-Src is an upstream mediator of aspirin/NSAID effects on NF-κB signalling and apoptosis in CRC cells and have relevance to the development of future chemotherapeutic/chemopreventative agents.
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Affiliation(s)
- Richard R W Brady
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
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Organ SL, Tong J, Taylor P, St-Germain JR, Navab R, Moran MF, Tsao MS. Quantitative phospho-proteomic profiling of hepatocyte growth factor (HGF)-MET signaling in colorectal cancer. J Proteome Res 2011; 10:3200-11. [PMID: 21609022 DOI: 10.1021/pr200238t] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the second leading cause of death from cancer. The MET receptor tyrosine kinase and/or its ligand HGF are frequently amplified or overexpressed in CRC. It is known that tyrosine phosphorylated proteins are involved in progression and metastasis of colorectal cancer; however, little is known about the MET phospho-proteome in CRC. High resolution mass spectrometry was used to characterize immunoaffinity-purified, phosphotyrosine (pY)-containing tryptic peptides of the MET-expressing CRC cell model, DLD1. A total of 266 unambiguously identified pY sites spanning 168 proteins were identified. Quantification of mass spectrometry ion currents identified 161 pY sites, including many not previously linked to MET signaling, that were modulated in abundance by HGF stimulation. Overlay of these data with protein-protein interaction data sets suggested that many of the identified HGF-modulated phospho-proteins may be directly or indirectly associated with MET. Analysis of pY sequence motifs indicated a prevalence of Src family kinase consensus sequences, and reciprocal signaling between Src and MET was confirmed by using selective small molecule inhibitors of these kinases. Therefore, using quantitative phospho-proteomics profiling, kinase modulation by ligand and inhibitors, and data integration, an outline of the MET signaling network was generated for the CRC model.
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Affiliation(s)
- Shawna L Organ
- Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, Canada
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Kumar S, Dimmock JR, Sharma RK. The potential use of N-myristoyltransferase as a biomarker in the early diagnosis of colon cancer. Cancers (Basel) 2011; 3:1372-82. [PMID: 22523637 PMCID: PMC3329441 DOI: 10.3390/cancers3011372] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2011] [Revised: 03/09/2011] [Accepted: 03/11/2011] [Indexed: 12/20/2022] Open
Abstract
Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% of cancer patients when initially diagnosed. The majority of colon cancers develop from noncancerous adenomatous polyps on the lining of the colon which grow over the years to become cancerous. If detected early, the surgical resections of the growth, often in combination with chemotherapy, significantly increases life expectancy. We have shown that the enzyme N-myristoyltransferase (NMT) which carries out lipid modification of several proteins (including many of those involved in oncogenesis) is expressed at higher levels in cancerous tissues from the colon. We have also shown that in peripheral blood mononuclear cells (PBMC) and bone marrow (BM) cells collected from colon cancer patients and from azoxymethane-induced rats the expression and localization of NMT is altered. We have observed strong positivity for NMT in immunohistochemical analysis for PBMC from colon cancer patients as compared to control groups. Furthermore, in the bone marrow (BM) mononuclear cells, NMT was found to be confined to the nuclei whereas in control groups it was observed to be located in the cytoplasm. In conclusion, this strikingly differential localization offers the basis of a potential investigational tool for screening or diagnosis of individuals at risk for or suspected of having colon cancer.
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Affiliation(s)
- Sujeet Kumar
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N OW8, Canada; E-Mail:
- Cancer Research Unit, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4 Canada
| | - Jonathan R Dimmock
- Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada; E-Mail:
| | - Rajendra K Sharma
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N OW8, Canada; E-Mail:
- Cancer Research Unit, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4 Canada
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Dunn EF, Iida M, Myers RA, Hintz KA, Campbell DA, Armstrong EA, Li C, Wheeler DL. Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. Oncogene 2011; 30:561-74. [PMID: 20956938 PMCID: PMC3025039 DOI: 10.1038/onc.2010.430] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Revised: 07/14/2010] [Accepted: 08/11/2010] [Indexed: 12/24/2022]
Abstract
KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux) in metastatic colorectal cancer (mCRC). This study sought to determine if KRAS mutant CRC lines could be sensitized to cetuximab using dasatinib (BMS-354825, Sprycel), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases (SFKs). We analyzed 16 CRC lines for: (1) KRAS mutation status, (2) dependence on mutant KRAS signaling and (3) expression level of epidermal growth factor receptor (EGFR) and SFKs. From these analyses, we selected three KRAS mutant (LS180, LoVo and HCT116) cell lines and two KRAS wild-type cell lines (SW48 and CaCo2). In vitro, using poly-D-lysine/laminin plates, KRAS mutant cell lines were resistant to cetuximab, whereas KRAS wild-type lines showed sensitivity to cetuximab. Treatment with cetuximab and dasatinib showed a greater antiproliferative effect on KRAS mutant lines when compared with either agent alone in vitro and in vivo. To investigate potential mechanisms for this antiproliferative response in the combinatorial therapy, we performed Human Phospho-Kinase Antibody Array analysis, measuring the relative phosphorylation levels of 39 intracellular proteins in untreated, cetuximab, dasatinib or the combinatorial treatment in the KRAS mutant lines LS180, LoVo and HCT116 cells. The results of this experiment showed a decrease in a broad spectrum of kinases centered on the β-catenin pathway, the mitogen-activated protein kinase (MAPK) pathway, AKT/mammalian target of rapamycin (mTOR) pathway and the family of signal transducers and activators of transcription (STATs) when compared with the untreated control or monotherapy treatments. Next, we analyzed tumor growth with cetuximab, dasatinib or their combination in vivo. KRAS mutant xenografts showed resistance to cetuximab therapy, whereas KRAS wild type demonstrated an antitumor response when treated with cetuximab. KRAS mutant tumors exhibited minimal response to dasatinib monotherapy. However, as in vitro, KRAS mutant lines exhibited a response to the combination of cetuximab and dasatinib. Combinatorial treatment of KRAS mutant xenografts resulted in decreased cell proliferation, as measured by Ki67, and higher rates of apoptosis, as measured by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). The data presented in this study indicate that dasatinib can sensitize KRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key signaling pathways. Furthermore, these results suggest that signaling via EGFR and SFKs may be necessary for cell proliferation and survival of KRAS mutant CRC tumors. These data strengthen the rationale for clinical trials combining cetuximab and dasatinib in the KRAS mutant CRC genetic setting.
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Affiliation(s)
- Emily F. Dunn
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Mari Iida
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Rebecca A. Myers
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Kylee A. Hintz
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - David A. Campbell
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Eric A. Armstrong
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Chunrong Li
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Deric L. Wheeler
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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Selvakumar P, Kumar S, Dimmock JR, Sharma RK. NMT1 (N-myristoyltransferase 1). ATLAS OF GENETICS AND CYTOGENETICS IN ONCOLOGY AND HAEMATOLOGY 2011; 15:570-575. [PMID: 22977462 PMCID: PMC3439497 DOI: 10.4267/2042/45997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ponniah Selvakumar
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N OW8, Canada (PS, SK, RKS); Cancer Research Unit, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada (PS, SK, RKS); Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada (JRD)
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Agrez M, Garg M, Dorahy D, Ackland S. Synergistic Anti-Tumor Effect of Cisplatin When Combined with an Anti-Src Kinase Integrin-Based Peptide. ACTA ACUST UNITED AC 2011. [DOI: 10.4236/jct.2011.23039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Boschelli F, Arndt K, Gambacorti-Passerini C. Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer 2010; 46:1781-9. [PMID: 20399641 DOI: 10.1016/j.ejca.2010.02.032] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Revised: 02/11/2010] [Accepted: 02/17/2010] [Indexed: 11/19/2022]
Abstract
Bosutinib (SKI-606) is an orally active Src and Abl kinase inhibitor presently in Phase III trials for treatment of chronic myelogenous leukaemia (CML), and in Phase II trials for treatment of breast cancer. Bosutinib is a potent antiproliferative and proapoptotic agent in CML cells and inhibits Bcr-Abl mediated signalling at nanomolar concentrations. Short-term administration of bosutinib causes regression of K562 and KU812 CML tumour xenografts. BaF3 murine myeloid cells expressing wild-type Bcr-Abl are sensitive to bosutinib treatment, as are BaF3 cells expressing many imatinib-resistant forms of Bcr-Abl. Recent studies indicate that bosutinib is active against a broader spectrum of kinases than originally believed. These additional inhibitory activities have interesting possibilities for further clinical development. This review will focus on preclinical studies supporting the clinical development of bosutinib for treatment of CML, with a discussion on the broader potential of this agent in other oncology indications.
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Affiliation(s)
- Frank Boschelli
- Department of Oncology, Wyeth Research (Wyeth Research is Now Pfizer Research), Pearl River, NY, USA.
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Lieu C, Kopetz S. The SRC family of protein tyrosine kinases: a new and promising target for colorectal cancer therapy. Clin Colorectal Cancer 2010; 9:89-94. [PMID: 20378502 PMCID: PMC3091503 DOI: 10.3816/ccc.2010.n.012] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Aberrant activation of the Src family of tyrosine kinases has been implicated in the development and progression of colorectal cancer (CRC). As a result, Src inhibitors are now being studied as possible therapeutic agents to treat metastatic disease. In this review, we discuss the effects of aberrant Src activation in CRC, Src as a target of single-agent drug therapy, and Src as a target of combination therapy with epidermal growth factor receptor inhibition and cytotoxic chemotherapy. The greatest potential for clinically relevant benefit most likely lies in combination regimens. Further evaluation with biomarkers will continue to define the molecular phenotype of patients with CRC who will benefit the most from Src-based therapy.
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Affiliation(s)
- Christopher Lieu
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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Maślikowski BM, Néel BD, Wu Y, Wang L, Rodrigues NA, Gillet G, Bédard PA. Cellular processes of v-Src transformation revealed by gene profiling of primary cells--implications for human cancer. BMC Cancer 2010; 10:41. [PMID: 20152043 PMCID: PMC2837010 DOI: 10.1186/1471-2407-10-41] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Accepted: 02/12/2010] [Indexed: 01/05/2023] Open
Abstract
Background Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. In this study, we took advantage of several strains of the Rous sarcoma virus (RSV) to characterize the patterns of v-Src-dependent gene expression in two different primary cell types, namely chicken embryo fibroblasts (CEF) and chicken neuroretinal (CNR) cells. We identified a common set of v-Src regulated genes and assessed if their expression is associated with disease-free survival using several independent human tumor data sets. Methods CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation. Microarray analysis was used to measure changes in gene expression and to define a common set of v-Src regulated genes (CSR genes) in CEF and CNR cells. A clustering enrichment regime using the CSR genes and two independent breast tumor data-sets was used to identify a 42-gene aggressive tumor gene signature. The aggressive gene signature was tested for its prognostic value by conducting survival analyses on six additional tumor data sets. Results The analysis of CEF and CNR cells revealed that cell transformation by v-Src alters the expression of 6% of the protein coding genes of the genome. A common set of 175 v-Src regulated genes (CSR genes) was regulated in both CEF and CNR cells. Within the CSR gene set, a group of 42 v-Src inducible genes was associated with reduced disease- and metastasis-free survival in several independent patient cohorts with breast or lung cancer. Gene classes represented within this group include DNA replication, cell cycle, the DNA damage and stress responses, and blood vessel morphogenesis. Conclusion By studying the v-Src-dependent changes in gene expression in two types of primary cells, we identified a set of 42 inducible genes associated with poor prognosis in breast and lung cancer. The identification of these genes provides a set of biomarkers of aggressive tumor behavior and a framework for the study of cancer cells characterized by elevated Src kinase activity.
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Affiliation(s)
- Bart M Maślikowski
- Department of Biology, McMaster University, 1280 Main street West, Hamilton, ON, L8S 4K1, Canada
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Hollande F, Pannequin J, Joubert D. The long road to colorectal cancer therapy: Searching for the right signals. Drug Resist Updat 2010; 13:44-56. [PMID: 20176501 DOI: 10.1016/j.drup.2009.01.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2009] [Revised: 01/25/2010] [Accepted: 01/26/2010] [Indexed: 02/07/2023]
Affiliation(s)
- Frédéric Hollande
- CNRS, UMR 5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France.
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Kopetz S, Lesslie DP, Dallas NA, Park SI, Johnson M, Parikh NU, Kim MP, Abbruzzese JL, Ellis LM, Chandra J, Gallick GE. Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res 2009; 69:3842-9. [PMID: 19383922 PMCID: PMC2709758 DOI: 10.1158/0008-5472.can-08-2246] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We show that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin-resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared with single-agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer and may provide the first indication of a molecular phenotype that might be susceptible to such combinations.
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Affiliation(s)
- Scott Kopetz
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
- Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center
| | - Donald P. Lesslie
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
- Department of Surgical Oncology, The University of Texas, M.D. Anderson Cancer Center
| | - Nikolas A. Dallas
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
| | - Serk I. Park
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
| | - Marjorie Johnson
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
- The Program in Cancer Biology, The University of Texas, Graduate School of Biomedical Sciences at Houston
| | - Nila U. Parikh
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
| | - Michael P. Kim
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
| | - James L. Abbruzzese
- Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center
| | - Lee M. Ellis
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
- Department of Surgical Oncology, The University of Texas, M.D. Anderson Cancer Center
| | - Joya Chandra
- Department of Pediatrics Research, The University of Texas, M.D. Anderson Cancer Center
| | - Gary E. Gallick
- Department of Cancer Biology, The University of Texas, M.D. Anderson Cancer Center
- The Program in Cancer Biology, The University of Texas, Graduate School of Biomedical Sciences at Houston
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35
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Serrels B, Serrels A, Mason SM, Baldeschi C, Ashton GH, Canel M, Mackintosh LJ, Doyle B, Green TP, Frame MC, Sansom OJ, Brunton VG. A novel Src kinase inhibitor reduces tumour formation in a skin carcinogenesis model. Carcinogenesis 2009; 30:249-57. [PMID: 19060248 DOI: 10.1093/carcin/bgn278] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The Src family tyrosine kinases are key modulators of cancer cell invasion and metastasis and a number of Src kinase inhibitors are currently in clinical development for the treatment of solid tumours. However, there is growing evidence that Src is also upregulated at very early stages of epithelial cancer development. We have investigated the role of Src in mouse skin, which is one of the most tractable models of epithelial homoeostasis and tumorigenesis. We found that Src protein expression and activity was regulated during the normal hair cycle and was increased specifically during the proliferative anagen phase and also in response to the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). AZD0530, a selective Src inhibitor, prevented the TPA-induced proliferation of basal keratinocytes both in vivo and in vitro. Moreover, treatment with AZD0530 reduced papilloma formation following the well-established 7,12-dimethylbenz(a)anthracene/TPA skin carcinogenesis protocol but did not inhibit the subsequent proliferation of the papillomas. Furthermore, AZD0530 did not alter the malignant conversion of papillomas to squamous cell carcinoma suggesting a role for Src in early tumour development in the skin carcinogenesis model, rather than at later stages of tumour progression. Src expression and activity were also seen in human actinic keratoses that are hyperproliferative pre-malignant skin lesions, indicating that Src may also play a role in the early stages of human skin tumour development. Thus, Src inhibitors such as AZD0530 may therefore have chemopreventative properties in patients with hyperproliferative epidermal disorders.
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Affiliation(s)
- Bryan Serrels
- Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK
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Stenzinger A, Schreiner D, Koch P, Hofer HW, Wimmer M. Cell and molecular biology of the novel protein tyrosine-phosphatase-interacting protein 51. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2009; 275:183-246. [PMID: 19491056 DOI: 10.1016/s1937-6448(09)75006-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This chapter examines the current state of knowledge about the expression profile, as well as biochemical properties and biological functions of the evolutionarily conserved protein PTPIP51. PTPIP51 is apparently expressed in splice variants and shows a particularly high expression in epithelia, skeletal muscle, placenta, and germ cells, as well as during mammalian development and in cancer. PTPIP51 is an in vitro substrate of Src- and protein kinase A, the PTP1B/TCPTP protein tyrosine phosphatases and interacts with 14-3-3 proteins, the Nuf2 kinetochore protein, the ninein-interacting CGI-99 protein, diacylglycerol kinase alpha, and also with itself forming dimers and trimers. Although the precise cellular function remains to be elucidated, the current data implicate PTPIP51 in signaling cascades mediating proliferation, differentiation, apoptosis, and motility.
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Affiliation(s)
- Albrecht Stenzinger
- Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany
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Budde RJA, McMurray JS, Saya H, Gallick GE, Levin VA. Discovery, Development, and Testing of Substrates and Inhibitors of pp60C-SRC. ACTA ACUST UNITED AC 2008. [DOI: 10.3109/13880209509067085] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Raymond J. A. Budde
- Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA
| | - John S. McMurray
- Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA
| | - Hideyuki Saya
- Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA
| | - Gary E. Gallick
- Department of Tumor Biology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA
| | - Victor A. Levin
- Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA
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Sun CK, Man K, Ng KT, Ho JW, Lim ZX, Cheng Q, Lo CM, Poon RT, Fan ST. Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. Carcinogenesis 2008; 29:2096-105. [PMID: 18765415 DOI: 10.1093/carcin/bgn203] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The aim of the current study is to elucidate the mechanism of proline-rich tyrosine kinase 2 (Pyk2)-mediated cell proliferation and invasiveness in hepatocellular carcinoma (HCC) cells. Human HCC cell lines PLC and MHCC97L were stably transfected with either full-length Pyk2 or C-terminal non-kinase region of Pyk2 (PRNK). Functional studies on cell proliferation and invasion were conducted in vitro by colony formation assay, adhesion assay, migration assay and wound-healing assay. For the in vivo study, an orthotopic nude mice liver tumor model was applied to investigate the effects of Pyk2 overexpression on tumor growth and metastasis. Overexpression of Pyk2 in PLC cells resulted in an upregulation of colony formation (P = 0.021) and adhesion toward laminin (P = 0.018). Pyk2 promoted wound recovery by stimulation of actin stress fiber polymerization. In the in vivo study, transfection of PRNK in MHCC97L cells significantly decreased tumor volume (P = 0.001) and the incidence of lung metastasis (P = 0.014). Overexpression of Pyk2 promoted the activation of c-Src, formation of Pyk2/c-Src complex and activated the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)-signaling pathway. Pyk2 upregulated the activation of ERK1/2 that is insensitive to MAPK/ERK kinase (MEK)1/2 inhibition. On the contrary, PRNK overexpression downregulated the activation of c-Src and ERK/MAPK-signaling pathways. Immunofluorescence staining showed that the focal adhesion localization of Pyk2 is a major determinant for c-Src and ERK/MAPK activation. In conclusion, our results showed that Pyk2 promoted cell proliferation and invasiveness by upregulation of the c-Src and ERK/MAPK-signaling pathways.
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Affiliation(s)
- Chris K Sun
- Department of Surgery and Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
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Kline CLB, Jackson R, Engelman R, Pledger WJ, Yeatman TJ, Irby RB. Src kinase induces tumor formation in the c-SRC C57BL/6 mouse. Int J Cancer 2008; 122:2665-73. [PMID: 18351644 DOI: 10.1002/ijc.23445] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Src kinase has been linked as a causative agent in the progression of a number of cancers including colon, breast, lung and melanoma. Src protein and activity levels are increased in colorectal cancer and liver metastases arising secondary to colon cancer. However, although Src protein is increased in colon cancer as early as the adenomatous polyp stage, a role for Src in carcinogenesis has not been established. We developed the c-SRC transgenic mouse in the C57BL/6 strain to address the issue of carcinogenesis in cells with high levels of Src expression. The transgene was constructed with the human c-SRC gene downstream of the mouse metallothionein promoter to create zinc inducible gene expression. In these C57BL/6 mice, Src protein was increased in a number of tissues both with and without zinc induction. No additional carcinogenic agent was administered. After 20 months, mice were assessed for tumor development in the liver and GI tract, as well as other organs. Of the mice with the transgene, 15% developed tumors in the liver while no tumors were detected in wild type C57BL/6 mice. A further study was conducted by crossing c-SRC C57BL/6 mice with p21 nullizygous mice to determine the effect of oncogene expression combined with inactivation of the tumor suppressor gene, p21. Addition of the c-SRC transgene to the p21-/- background increased tumor formation almost 3-fold, while it increased metastasis 6-fold. The data from our study show, for the first time, that Src kinase may play a role in carcinogenesis.
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Affiliation(s)
- Christina Leah B Kline
- Penn State Cancer Institute H072, Penn State College of Medicine, 500 University Drive, PO 850, Hershey, PA 17033, USA
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A redox-silent analogue of tocotrienol inhibits hypoxic adaptation of lung cancer cells. Biochem Biophys Res Commun 2007; 365:875-81. [PMID: 18042466 DOI: 10.1016/j.bbrc.2007.11.085] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2007] [Accepted: 11/19/2007] [Indexed: 11/23/2022]
Abstract
We have previously reported that a redox-silent analogue of alpha-tocotrienol (T3), 6-O-carboxypropyl-alpha-tocotrienol (T3E) shows more potential anti-carcinogenic property than T3 in a lung cancer cell (A549 cell). However, the mechanisms by which T3E exerts its potential anti-carcinogenic effect is still unclear. As tumor malignancy is associated with hypoxia adaptation, in this study, we examined whether T3E could suppress survival and invasion in A549 cells under hypoxia. Hypoxia treatment drastically-induced activation of the protein tyrosine kinase, Src, and its regulated signaling required for hypoxia adaptation of A549 tumor cells. The survival and invasion capacity of the tumor cells under hypoxia was suppressed by T3E via the inactivation of Src. More specifically, T3E-dependent inhibition of Src-induced Akt activation contributed to suppression of cell survival under hypoxia, and the reduction of fibrinolytic factors such as plasminogen activator-1(PAI-1) via the decrease of hypoxia-inducible factor-2alpha by T3E led to inhibition of hypoxic invasion. Overall these results suggest that T3E suppresses hypoxia adaptation of A549 cells by the inhibition in hypoxia-induced activation of Src signaling.
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Lapidus K, Wyckoff J, Mouneimne G, Lorenz M, Soon L, Condeelis JS, Singer RH. ZBP1 enhances cell polarity and reduces chemotaxis. J Cell Sci 2007; 120:3173-8. [PMID: 17878234 PMCID: PMC4956933 DOI: 10.1242/jcs.000638] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The interaction of beta-actin mRNA with zipcode-binding protein 1 (ZBP1) is necessary for its localization to the lamellipod of fibroblasts and plays a crucial role in cell polarity and motility. Recently, we have shown that low ZBP1 levels correlate with tumor-cell invasion and metastasis. In order to establish a cause and effect relationship, we expressed ZBP1 in a metastatic rat mammary adenocarcinoma cell line (MTLn3) that has low endogenous ZBP1 levels and delocalized beta-actin mRNA. This leads to localization of beta-actin mRNA, and eventually reduces the chemotactic potential of the cells as well as their ability to move and orient towards vessels in tumors. To determine how ZBP1 leads to these two apparently contradictory aspects of cell behavior--increased cell motility but decreased chemotaxis--we examined cell motility in detail, both in cell culture and in vivo in tumors. We found that ZBP1 expression resulted in tumor cells with a stable polarized phenotype, and reduced their ability to move in response to a gradient in culture. To connect these results on cultured cells to the reduced metastatic ability of these cells, we used multiphoton imaging in vivo to examine tumor cell behavior in primary tumors. We found that ZBP1 expression actually reduced tumor cell motility and chemotaxis, presumably mediating their decreased metastatic potential by reducing their ability to respond to signals necessary for invasion.
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Abstract
The Src family kinases (SFKs) are the largest family of nonreceptor protein tyrosine kinases and are responsible for signal transduction during many cellular activities, including differentiation, adhesion, and migration. Aberrant Src/SFK activity has been widely implicated in cancer development. Several lines of evidence indicate a role for SFKs in the development of prostate cancer, e.g. SFK overexpression in prostate cancer cell lines and tissues and reduced cancer cell proliferation, invasion, and migration following Src inhibition. In particular, Src may be involved in androgen-independent growth during advanced stages of disease. Src signaling is also a key pathway during normal and dysregulated bone functioning, and bone metastases are responsible for substantial morbidity in advanced prostate cancer. Src/SFK inhibition therefore represents a potentially useful therapeutic strategy for patients with various stages of prostate cancer. To date, four Src inhibitors have reached clinical trials. Of these, the broadest range of in vitro prostate cancer data are available for dasatinib, which inhibits several SFKs as well as other tyrosine kinases. Src inhibitors may be specifically evaluated in prostate cancer clinical trials in the near future.
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Affiliation(s)
- K Fizazi
- Department of Medicine, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France.
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Park SI, Shah AN, Zhang J, Gallick GE. Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors. Expert Opin Ther Targets 2007; 11:1207-17. [PMID: 17845146 DOI: 10.1517/14728222.11.9.1207] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aberrant expression or activation of protein tyrosine kinases, including Src and related Src family kinases, is a common occurrence in many human cancers, resulting in deregulation of expression of numerous mediators of cellular functions, including pro-angiogenic molecules. In addition, Src activation regulates vascular permeability of endothelial cells. How these processes contribute to tumor progression and metastasis are the subjects of this review. As Src-selective inhibitors have entered clinical trials for a number of solid tumors, further understanding of the roles of Src kinases in mediating tumor angiogenesis as well as modulating tumor/microenvironment interactions will provide insights into the best use of these inhibitors in treating patients afflicted with tumors in which Src is activated.
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Affiliation(s)
- Serk In Park
- The University of Texas M. D. Anderson Cancer Center, Department of Cancer Biology, Houston, TX 77030, USA
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Shah AN, Gallick GE. Src, chemoresistance and epithelial to mesenchymal transition: are they related? Anticancer Drugs 2007; 18:371-5. [PMID: 17351389 DOI: 10.1097/cad.0b013e32801265d7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Src family of nonreceptor tyrosine kinases regulates numerous cellular processes, including proliferation, differentiation, migration, survival and angiogenesis. In solid tumors, Src is frequently aberrantly active, and promotes tumor progression and metastasis. Although multiple Src functions may contribute to metastasis, recently Src has been shown to play a role in epithelial to mesenchymal transition. Increased Src activity promotes this process and inhibition of Src suppresses epithelial to mesenchymal transition. Although the molecular events causing epithelial to mesenchymal transition are becoming well defined, the processes in tumor cells that trigger the onset of this phenotype remain unclear. Recent studies have associated epithelial to mesenchymal transition with the development of chemoresistance. Src has also been shown to be involved in chemoresistance of cancer cells. The activation of Src in chemoresistant cells is related to an increase in motility, invasiveness and detachment, all phenotypes characteristic both of Src activation and of epithelial to mesenchymal transition. This review focuses on upregulation of Src in cancer as it relates to chemoresistance and epithelial to mesenchymal transition.
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Affiliation(s)
- Ami N Shah
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Ly QP, Yeatman TJ. Clinical relevance of targeted interference with Src-mediated signal transduction events. Recent Results Cancer Res 2007; 172:169-88. [PMID: 17607941 DOI: 10.1007/978-3-540-31209-3_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Affiliation(s)
- Quan P Ly
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
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Selvakumar P, Lakshmikuttyamma A, Shrivastav A, Das SB, Dimmock JR, Sharma RK. Potential role of N-myristoyltransferase in cancer. Prog Lipid Res 2007; 46:1-36. [PMID: 16846646 DOI: 10.1016/j.plipres.2006.05.002] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colorectal cancer is the second leading cause of malignant death, and better preventive strategies are needed. The treatment of colonic cancer remains difficult because of the lack of effective chemotherapeutic agents; therefore it is important to continue to search for cellular functions that can be disrupted by chemotherapeutic drugs resulting in the inhibition of the development and progression of cancer. The current knowledge of the modification of proteins by myristoylation involving myristoyl-CoA: protein N-myristoyltransferase (NMT) is in its infancy. This process is involved in the pathogenesis of cancer. We have reported for the first time that NMT activity and protein expression were higher in human colorectal cancer, gallbladder carcinoma and brain tumors. In addition, an increase in NMT activity appeared at an early stage in colonic carcinogenesis. It is conceivable therefore that NMT can be used as a potential marker for the early detection of cancer. These observations lead to the possibility of developing NMT specific inhibitors, which may be therapeutically useful. We proposed that HSC70 and/or enolase could be used as an anticancer therapeutic target. This review summarized the status of NMT in cancer which has been carried in our laboratory.
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Affiliation(s)
- Ponniah Selvakumar
- Department of Pathology and Laboratory Medicine, College of Medicine, and Health Research Division, Saskatchewan Cancer Agency, University of Saskatchewan, 20 Campus Drive, Saskatoon, Sask., Canada S7N 4H4
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Homsi J, Cubitt C, Daud A. The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets 2006; 11:91-100. [PMID: 17150037 DOI: 10.1517/14728222.11.1.91] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Although Src was the first oncogene to be discovered as the transforming protein of the Rous sarcoma virus almost three decades ago, the role of Src and the Src family kinases in human oncogenesis is still not completely understood. Recent studies have shown that Src regulates cell adhesion, invasiveness and motility in cancer cells and in tumor vasculature, rather than directly influencing cell replication. The role of the Src family kinases in human cancer is evolving and elevated levels of Src kinase activity have been reported in a number of human cancers in vitro and in vivo. Src expression and activity are increased in melanoma cell lines and in melanoma tumors in vivo. Src can activate STAT3, STAT5 and other downstream targets in melanoma. Src and STAT3 are expressed in their activated forms in both primary and metastatic melanoma in humans, although the expression level is variable. Cumulatively, these data mark Src signaling as attractive therapeutic targets in melanoma. Studies are currently underway with novel Src inhibitors in melanoma and in other tumor types.
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Affiliation(s)
- Jade Homsi
- Cutaneous Therapeutic Program, H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, USA
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Serrels A, Macpherson IRJ, Evans TRJ, Lee FY, Clark EA, Sansom OJ, Ashton GH, Frame MC, Brunton VG. Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. Mol Cancer Ther 2006; 5:3014-22. [PMID: 17148760 DOI: 10.1158/1535-7163.mct-06-0382] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Elevated levels of Src kinase expression have been found in a variety of human epithelial cancers. Most notably in colon cancer, elevated Src expression correlates with malignant potential and is also associated with metastatic disease. Dasatinib (BMS-354825) is a novel, orally active, multi-targeted kinase inhibitor that targets Src family kinases and is currently under clinical evaluation for the treatment of solid tumors. However, the effects of dasatinib on epithelial tumors are not fully understood. We show that concentrations of dasatinib that inhibit Src activity do not inhibit proliferation in 10 of 12 colon cancer cells lines. However, inhibition of integrin-dependent adhesion and migration by dasatinib correlated with inhibition of Src activity, suggesting that dasatinib may have anti-invasive or anti-metastatic activity and antiproliferative activity in epithelial tumors. Using phospho-specific antibodies, we show that inhibition of Src activity in colon cancer cell lines correlates with reduced phosphorylation of focal adhesion kinase and paxillin on specific Src-dependent phosphorylation sites. We have validated the use of phospho-specific antibodies against Src Tyr(419) and paxillin Tyr(118) as biomarkers of dasatinib activity in vivo. Colon carcinoma-bearing mice treated with dasatinib showed a decrease in both phospho-Src Tyr(419) and phospho-paxillin Tyr(118) in peripheral blood mononuclear cells, which correlated with inhibition of Src activity in the colon tumors. Thus, peripheral blood mononuclear cells may provide a useful surrogate tissue for biomarker studies with dasatinib using inhibition of Src Tyr(419) and paxillin Tyr(118) phosphorylation as read-outs of Src activity.
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Affiliation(s)
- Alan Serrels
- The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, G61 1BD, United Kingdom
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Affiliation(s)
- Justin M Summy
- Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA
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Hagiwara H, Sato H, Shirai S, Kobayashi S, Fukumoto K, Ishida T, Seki T, Ariga T, Yano T. Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells. Life Sci 2006; 78:2249-54. [PMID: 16289236 DOI: 10.1016/j.lfs.2005.09.036] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2005] [Accepted: 09/13/2005] [Indexed: 11/17/2022]
Abstract
Fibrinolytic factors have an important role in tumor progression through the degradation of extracellular matrix. The increased levels of urokinase-type plasminogen activator (uPA), uPA-receptor (uPAR) and type-1 PA inhibitor (PAI-1) are reported in human renal cell carcinoma (RCC). Connexin (Cx) gene, a member of gap junction, is known to act as a tumor suppressor gene. We have reported that Cx32 improves malignant phenotypes of metastatic RCC cells via the inhibition of Src-dependent signaling. In this study, we examined the effect of expression of Cx32 gene on the production of uPA, uPAR and PAI-1, and on the induction of PAI-1 stimulated by hypoxia in a human metastatic RCC cell line, Caki-1 cells. Cx32 expression decreased both mRNA level and production of PAI-1, uPA and uPAR in Caki-1 cells. Cx32 also decreased hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha mRNA level. PP1, a Src inhibitor, significantly decreased PAI-1, uPA, uPAR and HIF-alpha mRNA levels in Caki-1 cells. Furthermore, Cx32 suppressed the induction of HIF-2alpha protein in Caki-1 cells under hypoxia. PAI-1 mRNA level in Cx32-transfected Caki-1 cells was lower than that of mock transfectant under hypoxic conditions. These results suggest that Cx32 might reduce PAI-1, uPA and uPAR production in metastatic RCC cells via the inhibition of Src-dependent induction of HIF-1alpha and HIF-2alpha gene expression and that Cx32 might suppress hypoxia-inducible gene expression under hypoxic conditions.
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Affiliation(s)
- Hiromi Hagiwara
- Department of Food Science Research for Health, National Institute of Health and Nutrition, Toyama, Shinjuku, Tokyo, Japan.
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