Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment
Abstract Background Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood. Methods The expression of PKD...
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| Format: | Article |
| Language: | English |
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BMC
2019-03-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1118-y |
| _version_ | 1817988473946112000 |
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| author | Wanfu Xu Jiabi Qian Fangyin Zeng Songyu Li Wenjing Guo Liping Chen Guihuan Li Zhishuai Zhang Qiming Jane Wang Fan Deng |
| author_facet | Wanfu Xu Jiabi Qian Fangyin Zeng Songyu Li Wenjing Guo Liping Chen Guihuan Li Zhishuai Zhang Qiming Jane Wang Fan Deng |
| author_sort | Wanfu Xu |
| collection | DOAJ |
| description | Abstract Background Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood. Methods The expression of PKD, mast cells and microvessel density were examined by IHC. The clinical significance was determined by statistical analyses. The biological function of PKD and the underlying mechanisms were investigated using in vitro and in vivo models. Results PKD2/3 contributed to MCs recruitment and tumor angiogenesis in the prostate cancer microenvironment. Clinical data showed that increased activation of PKD at Ser744/748 in prostate cancer was correlated with mast cell infiltration and microvascular density. PKD2/3 silencing of prostate cancer cells markedly decreased MCs migration and tube formation of HUVEC cells. Moreover, PKD2/3 depletion not only reduced SCF, CCL5 and CCL11 expression in prostate cancer cells but also inhibited angiogenic factors in MCs. Conversely, exogenous SCF, CCL5 and CCL11 reversed the effect on MCs migration inhibited by PKD2/3 silencing. Mechanistically, PKD2/3 interacted with Erk1/2 and activated Erk1/2 or NF-κB signaling pathway, leading to AP-1 or NF-κB binding to the promoter of scf, ccl5 and ccl11. Finally, PKD-specific inhibitor significantly reduced tumor volume and tumor growth in mice bearing RM-1 prostate cancer cells, which was attributed to attenuation of mast cell recruitment and tumor angiogenesis. Conclusions These results demonstrate a novel PKDs function that contributes to tumor angiogenesis and progression through mast cells recruitment in prostate cancer microenvironment. |
| first_indexed | 2024-04-14T00:34:35Z |
| format | Article |
| id | doaj.art-03c2a549bbee49fe9741ec4d4b36ece3 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-14T00:34:35Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-03c2a549bbee49fe9741ec4d4b36ece32022-12-22T02:22:24ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-03-0138111310.1186/s13046-019-1118-yProtein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironmentWanfu Xu0Jiabi Qian1Fangyin Zeng2Songyu Li3Wenjing Guo4Liping Chen5Guihuan Li6Zhishuai Zhang7Qiming Jane Wang8Fan Deng9Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical UniversityDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicineDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityAbstract Background Mast cells are being increasingly recognized as critical components in the tumor microenvironment. Protein Kinase D (PKD) is essential for the progression of prostate cancer, but its role in prostate cancer microenvironment remains poorly understood. Methods The expression of PKD, mast cells and microvessel density were examined by IHC. The clinical significance was determined by statistical analyses. The biological function of PKD and the underlying mechanisms were investigated using in vitro and in vivo models. Results PKD2/3 contributed to MCs recruitment and tumor angiogenesis in the prostate cancer microenvironment. Clinical data showed that increased activation of PKD at Ser744/748 in prostate cancer was correlated with mast cell infiltration and microvascular density. PKD2/3 silencing of prostate cancer cells markedly decreased MCs migration and tube formation of HUVEC cells. Moreover, PKD2/3 depletion not only reduced SCF, CCL5 and CCL11 expression in prostate cancer cells but also inhibited angiogenic factors in MCs. Conversely, exogenous SCF, CCL5 and CCL11 reversed the effect on MCs migration inhibited by PKD2/3 silencing. Mechanistically, PKD2/3 interacted with Erk1/2 and activated Erk1/2 or NF-κB signaling pathway, leading to AP-1 or NF-κB binding to the promoter of scf, ccl5 and ccl11. Finally, PKD-specific inhibitor significantly reduced tumor volume and tumor growth in mice bearing RM-1 prostate cancer cells, which was attributed to attenuation of mast cell recruitment and tumor angiogenesis. Conclusions These results demonstrate a novel PKDs function that contributes to tumor angiogenesis and progression through mast cells recruitment in prostate cancer microenvironment.http://link.springer.com/article/10.1186/s13046-019-1118-yProtein kinase D(PKD)Mast cells(MCs)AngiogenesisProstate cancer |
| spellingShingle | Wanfu Xu Jiabi Qian Fangyin Zeng Songyu Li Wenjing Guo Liping Chen Guihuan Li Zhishuai Zhang Qiming Jane Wang Fan Deng Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment Journal of Experimental & Clinical Cancer Research Protein kinase D(PKD) Mast cells(MCs) Angiogenesis Prostate cancer |
| title | Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment |
| title_full | Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment |
| title_fullStr | Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment |
| title_full_unstemmed | Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment |
| title_short | Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment |
| title_sort | protein kinase ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment |
| topic | Protein kinase D(PKD) Mast cells(MCs) Angiogenesis Prostate cancer |
| url | http://link.springer.com/article/10.1186/s13046-019-1118-y |
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