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

Bullock, Nicholas; Potts, Jonathan R.; Simpkin, Andrew; Koupparis, Anthony; Harper, Steven J.; Oxley, Jon; Oltean, Sebastian

doi:10.1136/jclinpath-2015-203125

Cited by 36 publications

(33 citation statements)

References 11 publications

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“…However, as SILAC approaches measure protein abundance by MS1 quantitation, they can result in lower overall protein coverage (50). Thus, a potential limitation to measuring kinase levels in heterogeneous tissues using the Q-MIBs approach is that we can only quantitate with high confidence those kinases that have a matching Mis-spliced gene targets following SPHINX31-treatment were enriched in VEGF pathways and angiogenesis, consistent with recent studies showing SRPK1 function has been shown to block splicing of VEGF 165a to VEGF 165b reducing angiogenesis in cells and tumor models (38).…”

Section: Discussionsupporting

confidence: 70%

“…6D). Consistent with these findings, inhibition of SRPK1 has been previously shown to block splicing of VEGF 165a to VEGF 165b impacting Vegf signaling and angiogenesis (38).…”

Section: Srpk1 Inhibition Promotes Alternative Splicing Impairing Sursupporting

confidence: 65%

“…Overexpression of SRPK1 has been observed in highly aggressive breast cancers, such as triple negative breast cancers (TNBCs) and may be linked to development of resistance to therapy, highlighting SRPK1 as an attractive therapeutic target (37). SRPK1 has been shown to be essential for mRNA alternative splicing in cells and blockade of SRPK1 function alters several oncogenic processes including angiogenesis, migration/invasion, proliferation, cancer stem cell (CSC) phenotype, and sensitivity to chemotherapy (38).…”

Section: Srpk1 Is Overexpressed In Endometrial Tumors and Represents mentioning

confidence: 99%

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Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Johnson

Kumar

Kurimchak

et al. 2020

Preprint

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Protein kinases (collectively, termed the kinome) represent one of the most tractable drug targets in the pursuit of new and effective cancer treatments. However, less than 20% of the kinome is currently being explored as primary targets for cancer therapy, leaving the majority of the kinome untargeted for drug therapy. Chemical proteomics approaches such as Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS) have been developed that measure the

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Section: Discussionsupporting

confidence: 70%

“…6D). Consistent with these findings, inhibition of SRPK1 has been previously shown to block splicing of VEGF 165a to VEGF 165b impacting Vegf signaling and angiogenesis (38).…”

Section: Srpk1 Inhibition Promotes Alternative Splicing Impairing Sursupporting

confidence: 65%

Section: Srpk1 Is Overexpressed In Endometrial Tumors and Represents mentioning

confidence: 99%

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Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Johnson

Kumar

Kurimchak

et al. 2020

Preprint

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“…Approach Followed (Testing on Histology Samples/Blood; Data Mining) Level Tested (mRNA; Protein) Clinical Significance Reference Lung data mining; histology samples mRNA; protein ↑SRPK1 was found in NSCLC and was associated with higher tumor stage and shorter survival [29] histology samples mRNA; protein ↑SRPK1 was found in NSCLC [30] data mining mRNA ↑SRPK1 was found in lung adenocarcinoma (a NSCLC histologic type) [31] Breast histology samples mRNA; protein ↑SRPK1 was found in breast cancer and was associated with higher tumor stage and shorter survival [32] histology samples; data mining mRNA; protein ↑SRPK1 was associated with shorter survival in breast cancer and metastatic disease to the lungs and brain [33] data mining mRNA ↑SRPK1 was associated with shorter survival in HER2-negative breast cancer patients treated with chemotherapy [34] histology samples protein ↑SRPK1 was found in breast cancer [35] histology samples protein ↑SRPK1 was found in breast cancer [22] histology samples protein ↑SRPK1 was found in breast cancer and was associated with higher tumor grade [36] Prostate histology samples protein ↑SRPK1 was found in prostate cancer and its precursor (PIN) [26] histology samples protein ↑SRPK1 was found in prostate cancer and was associated with higher stage [37] Colorectal histology samples protein ↑SRPK1 was found in colon cancer and its precursor (adenoma) [22] histology samples protein ↑SRPK1 was found in colon cancer and was associated with higher tumor grade [36] histology samples mRNA; protein ↑SRPK1 was found in colorectal cancer and was associated with higher tumor stage and shorter survival [38] histology samples mRNA; protein ↑SRPK1 was found in colorectal cancer and was associated with higher tumor stage and shorter survival [39] histology samples mRNA ↑SRPK1 was found in colorectal cancer and its precursor (adenoma) [31] histology samples protein ↑SRPK1 and p-AKT were found in colon cancer [40] Stomach data mining mRNA ↑SRPK1 was found in gastric cancer [31] histology samples protein ↑SRPK1 was found in gastric cancer and was associated with higher tumor stage and shorter survival [41] histology samples protein ↑SRPK1 was found in gastric cancer [42] histology samples mRNA; protein ↑SRPK1 was found in gastric cancer and was associated with higher tumor stage and shorter survival [43] Liver histology samples mRNA; protein ↑SRPK1 was associated with higher stage and shorter survival; SRPK1 expression was inversely correlated with miR-1296 expression…”

Section: Cancer Type (Primary Location)mentioning

confidence: 99%

Serine-Arginine Protein Kinase 1 (SRPK1) as a Prognostic Factor and Potential Therapeutic Target in Cancer: Current Evidence and Future Perspectives

Nikas

Themistocleous

Paschou

et al. 2019

Cells

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Cancer, a heterogeneous disease composed of tumor cells and microenvironment, is driven by deregulated processes such as increased proliferation, invasion, metastasis, angiogenesis, and evasion of apoptosis. Alternative splicing, a mechanism led by splicing factors, is implicated in carcinogenesis by affecting any of the processes above. Accumulating evidence suggests that serine-arginine protein kinase 1 (SRPK1), an enzyme that phosphorylates splicing factors rich in serine/arginine domains, has a prognostic and potential predictive role in various cancers. Its upregulation is correlated with higher tumor staging, grading, and shorter survival. SRPK1 is also highly expressed in the premalignant changes of some cancers, showing a potential role in the early steps of carcinogenesis. Of interest, its downregulation in preclinical models has mostly been tumor-suppressive and affected diverse processes heterogeneously, depending on the oncogenic context. In addition, targeting SRPK1 has enhanced sensitivity to platinum-based chemotherapy in some cancers. Lastly, its aberrant function has been noted not only in cancer cells but also in the endothelial cells of the microenvironment. Although the aforementioned evidence seems promising, more studies are needed to reinforce the use of SRPK1 inhibitors in clinical trials. major area of research in the field of intratumor heterogeneity, while their presence is associated with cancer recurrence, metastasis, and resistance to chemotherapy [7].Cancer prognosis depends on multiple factors that affect survival. Tumor staging, traditionally performed with the TNM system, is the most important prognostic factor. It refers to the size of the tumor (T), also the extent of its spread to the regional lymph nodes (N) or distant metastatic sites (M) [8,9]. Grading refers to the histologic picture of the tumor, more specifically, how closely it looks compared to the normal tissue it derives from (differentiation) [10,11]. Both the presence of distant metastases (e.g., in lungs, brain, liver, bones) and poor differentiation are associated with a dismal prognosis [9,11]. The molecular subtype of specific cancers is also critical for cancer survival. For instance, breast cancer has diverse intrinsic subtypes-luminal A and B, human epidermal growth factor receptor 2-enriched (HER2-enriched), and basal-like-that directly impact prognosis [12][13][14]. Luminal breast cancers are most commonly hormone-positive, overexpressing estrogen receptors (ER), and are associated with a better prognosis than HER2-enriched or basal-like breast cancers (BLBCs) [12][13][14][15]. BLBCs, which most commonly present with a triple-negative phenotype, have been linked with the worst prognosis and highest metastatic potential of all breast cancer molecular subtypes [13,16,17].Alternative splicing is the process that removes introns and adds exons in various combinations resulting in multiple mRNA products hence protein transcripts. As a result, it maintains the protein diversity and cellular homeostasis [18]. The...

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“…54,55 The lower availability results in alterations in AS of specific genes regulated by MBNL, which contribute to myotonic dystrophy pathogenesis. SRPK1, a kinase that phosphorylates SR-proteins (the class of splice factors mentioned above), is overexpressed in several cancers [56][57][58] and also in DenysDrash syndrome, associated renal failure, and increased incidence of Wilms tumors. 59 SRPK1 is a determinant of angiogenesis through modulation of VEGF-A splicing and its abnormal expression maintains a pathologic loop by promoting proangiogenic and propermeability VEGF-A isoforms.…”

Section: Splice Factors or Splicing-specific Kinases Are Deregulated mentioning

confidence: 99%

Alternative Splicing in CKD

Stevens

Oltean

2016

JASN

Self Cite

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Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with $94% of multiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit.

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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

Cited by 36 publications

References 11 publications

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Serine-Arginine Protein Kinase 1 (SRPK1) as a Prognostic Factor and Potential Therapeutic Target in Cancer: Current Evidence and Future Perspectives

Alternative Splicing in CKD

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