The hypothesis posits that inhibiting SRPK1 (Serine/Arginine Protein Kinase 1) in cancer cells will restore normal splicing patterns by reducing the hyperphosphorylation of SRSF1 (Serine/Arginine Rich Splicing Factor 1), ultimately leading to decreased tumor growth. This is based on the understanding that aberrant splicing is a hallmark of many cancers, contributing to tumorigenesis and malignancy.
1. **Role of SRPK1**: SRPK1 is a kinase that phosphorylates SRSF1, which is crucial for its function in splicing regulation. Phosphorylation of SRSF1 enhances its activity and alters its binding to pre-mRNA, promoting the inclusion of oncogenic splice variants that favor tumor growth .
2. **Impact of SRSF1 Phosphorylation**: Hyperphosphorylation of SRSF1 leads to the production of pro-tumorigenic splice variants, such as those involved in angiogenesis (e.g., VEGF-A isoforms) .
Inhibition of SRPK1 has been shown to switch splicing towards anti-angiogenic isoforms of VEGF, thereby reducing tumor growth in various cancer models .
By restoring normal splicing patterns through SRPK1 inhibition, it is hypothesized that cancer cells will exhibit reduced proliferation and enhanced sensitivity to apoptosis, leading to decreased tumor growth. This approach could provide a novel therapeutic strategy that targets the splicing machinery rather than traditional pathways, potentially resulting in fewer side effects and improved patient outcomes.
The hypothesis that inhibiting SRPK1 can restore normal splicing patterns and reduce tumor growth is supported by emerging evidence linking splicing dysregulation to cancer progression. Further research is needed to validate these findings and explore the therapeutic potential of SRPK1 inhibitors in clinical settings.