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

Abstract

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.

Keywords: TNM staging; alternative splicing; angiogenesis; apoptosis; cancer survival; chemotherapy resistance; metastasis; personalized medicine; prognosis; serine-arginine protein kinase 1 (SRPK1).

Figure 1

This figure shows the effect of serine-arginine protein kinase 1 downregulation (↓SRPK1) on distinct oncogenic processes, highlighting its potential role as a therapeutic target in various malignancies. Fourteen different cancer types are shown. Arrows and inhibition symbols represent promotion or suppression, respectively, of the pointed processes after SRPK1 downregulation in each one of the listed cancer types. Red color means the specific interaction between SRPK1 and the pointed process is discussed in the literature. Gray color could mean that the interaction is not described, described but not activated (e.g., ↓SRPK1 doesn’t involve proliferation, migration, and invasion in prostate cancer or proliferation in melanoma) or described with an opposite result in the literature (e.g., ↓SRPK1 enhances resistance, rather than sensitivity to chemotherapy in gliomas).

Figure 1

This figure shows the effect of serine-arginine protein kinase 1 downregulation (↓SRPK1) on distinct oncogenic processes, highlighting its potential role as a therapeutic target in various malignancies. Fourteen different cancer types are shown. Arrows and inhibition symbols represent promotion or suppression, respectively, of the pointed processes after SRPK1 downregulation in each one of the listed cancer types. Red color means the specific interaction between SRPK1 and the pointed process is discussed in the literature. Gray color could mean that the interaction is not described, described but not activated (e.g., ↓SRPK1 doesn’t involve proliferation, migration, and invasion in prostate cancer or proliferation in melanoma) or described with an opposite result in the literature (e.g., ↓SRPK1 enhances resistance, rather than sensitivity to chemotherapy in gliomas).

Figure 2

SRPK1 (serine-arginine protein kinase 1) overexpression deregulates alternative splicing and promotes cancer through distinct oncogenic processes such as angiogenesis and apoptosis. (a) SRPK1 overexpression switches VEGF (vascular endothelial growth factor) alternative splicing towards the proangiogenic VEGF isoform(s) in prostate cancer, colorectal cancer, melanoma, and tumor endothelium. (b) SRPK1 overexpression switches IR (insulin receptor) and MCL-1 (myeloid cell leukemia-1) alternative splicing towards the antiapoptotic isoforms IR-A and MCL-1L, respectively, in hormone-positive breast cancer.