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. 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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“…The drug, SCO-101, binds to ABCG2 and leads to its degradation. It also inhibits the function of the SRPK-1 kinase which has been suggested to be involved in drug resistance [30]. SCO-101 was in four clinical phase I studies shown to be a safe oral drug with only limited toxicity [31].…”

Interplay Between CMGC Kinases Targeting SR Proteins and Viral Replication: Splicing and Beyond

“…Because of their multiple activities, aberrant expression and/or activity of all these kinases have been frequently associated to cancer development. For studies regarding the role of these kinases in cancer, we refer the interested readers to dedicated reviews and references therein ( Czubaty and Piekielko-Witkowska, 2017 ; Nikas et al, 2019 ; Laham et al, 2020 ).…”

Abnormal alternative splicing promotes tumor resistance in targeted therapy and immunotherapy

“…Similarly, the inhibition of SRPK1 could simultaneously influence a variety of oncogenic processes, including angiogenesis, apoptosis, proliferation, migration, invasion, and metastasis. Interestingly, targeting SRPK1 could enhance sensitivity to platinum-based chemotherapy in certain carcinomas [96] . Splicing-correcting therapy uses splice-switching oligonucleotides (SSOs) to target splicing defects, which are often used to treat neuromuscular disorders in clinical practice [97] .…”