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Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion.

ABSTRACT: Vascular endothelial growth factor (VEGF) undergoes alternative splicing to produce both proangiogenic and antiangiogenic isoforms. Preferential splicing of proangiogenic VEGF is determined by serine-arginine protein kinase 1 (SRPK1), which is upregulated in a number of cancers. In the present study, we aimed to investigate SRPK1 expression in prostate cancer (PCa) and its association with cancer progression. SRPK1 expression was assessed using immunohistochemistry of PCa tissue extracted from radical prostatectomy specimens of 110 patients. SRPK1 expression was significantly higher in tumour compared with benign tissue (p<0.00001) and correlated with higher pT stage (p=0.004), extracapsular extension (p=0.003) and extracapsular perineural invasion (p=0.008). Interestingly, the expression did not correlate with Gleason grade (p=0.21), suggesting that SRPK1 facilitates the development of a tumour microenvironment that favours growth and invasion (possibly through stimulating angiogenesis) while having little bearing on the morphology or function of the tumour cells themselves.

SUBMITTER: Bullock N

PROVIDER: S-EPMC4752636 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion.

Bullock Nicholas N Potts Jonathan J Simpkin Andrew J AJ Koupparis Anthony A Harper Steve J SJ Oxley Jon J Oltean Sebastian S

Journal of clinical pathology 20151023 2

Vascular endothelial growth factor (VEGF) undergoes alternative splicing to produce both proangiogenic and antiangiogenic isoforms. Preferential splicing of proangiogenic VEGF is determined by serine-arginine protein kinase 1 (SRPK1), which is upregulated in a number of cancers. In the present study, we aimed to investigate SRPK1 expression in prostate cancer (PCa) and its association with cancer progression. SRPK1 expression was assessed using immunohistochemistry of PCa tissue extracted from r ...[more]

PMID: 26500332

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Project description:Although devascularization caused by antiangiogenic therapy limits tumor growth, the benefits of antiangiogenic therapy are often transient, with tumor growth typically resuming through adaptive responses that need further characterization. Recent reports indicate that hypoxia in tumor microenvironments induces autophagy, a lysosomal degradation pathway that may promote tumor cell survival. We investigated the hypothesis that antiangiogenic therapy leads to hypoxia, which induces tumor cell autophagy as a cytoprotective adaptive response promoting evasion to antiangiogenic therapy. We found that patient specimens from glioblastomas evasive to bevacizumab exhibited nearly 80% more hypoxia than did pretreatment specimens from the same patients. Hypoxia (1% oxygen) induced autophagy in several primary glioblastoma cells and cell lines. Selective autophagy occurred independent of HIF-1?/AMPK hypoxia-upregulated pathways, while nonselective autophagy depended on both. Autophagy inhibitors transitioned hypoxic glioblastoma cells from autophagy to nonapoptotic cell death. Patient specimens from glioblastomas evading antiangiogenic therapy expressed 55% more autophagy-related BNIP3 than did pretreatment specimens from the same patients, with BNIP3 expression localizing to the increased hypoxic areas seen in the glioblastomas that evaded antiangiogenic therapy. Human glioblastoma xenografts exhibited persistent growth inhibition when treated with autophagy inhibitor chloroquine plus antiangiogenic bevacizumab; chloroquine prevented the evasive hypoxia-associated growth seen with bevacizumab alone and reversed the more than 2-fold increased expression of autophagy mediator BNIP3 seen in xenografts growing during bevacizumab monotherapy. These findings suggest that hypoxia-mediated autophagy promotes tumor cell survival after antiangiogenic therapy, a novel adaptive response to antiangiogenic therapy that can be pharmacologically disrupted to allow antiangiogenic therapy to fulfill its therapeutic promise.

Dataset Information

Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion.

Publications

Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion.

Similar Datasets

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