SRPK1 (SRSF Protein Kinase 1)

Our results link replication stress, kinase signaling, and RNA processing across genetically diverse clonal states, highlighting potential therapeutic approaches at these nodes. While most splicing changes differ by splicing factor (SF) mutation, certain retained introns are common across subtypes.Changes in RI are bidirectional, concordant across mutant groups, and mirrors SRSF1 loss.SF mutations activate DDR, triggering an AMPKα/AKT imbalance that culminates in SRSF1 hypophosphorylation.Relieving R-loop induced DDR restores SRSF1 phosphorylation and reverses RI.

Well-tempered metadynamics confirmed unbinding PMF of -23.71 kcal mol-1 for CNP0199214 and -14.81 kcal mol-1 for MSC1186 (Lig_ref) to a relative difference in PMF of the screened ligand to be ≈7 kcal mol-1. A probable gating mechanism is observed for the reference ligand (Lig_ref) at the protein interface resulting multiple minima in PMF, whereas Lig_4 (CNP0199214) exhibits greater affinity toward the active pocket and therefore choice for a potent compound.

This study demonstrated that SRPK1 inhibition alters lncRNA expression and splicing-related events in PCa. These findings highlight SPHINX31's potential as a therapeutic agent, especially in combination with treatments like Olaparib, necessitating further optimization for selectivity and reduced off-target effects.

In this study, we report the design, synthesis, and preliminary biological evaluation of two hybrid molecules, geo15 and geo140, which combine known SRPK1 inhibitors with the antimetabolites gemcitabine and 5-fluorouracil (5-FU), respectively. Interestingly, treatment with geo140 did not appear to alter the overall SRPK1 distribution in interphase cells but resulted in a notable increase of mitotic cells that displayed a substantial accumulation of SRPK1, thus suggesting that the hybrid compound may have an impact on cell cycle progression. This work supports the potential of molecular hybridization as a strategy for the development of novel SRPK1-targeting anticancer agents.

It was also observed that C1orf122 significantly activated the PI3K/AKT/GSK3β signaling pathway via SRPK1. To the best of our knowledge, this is the first study to demonstrate the involvement of the C1orf122-SRPK1-PI3K/AKT/GSK3β axis in HCC growth.

As for GH-secreting primary cultures from GH-PitNETs, SRPIN340 incubation resulted in reduced VEGF165a expression (-50.6% vs control cells) and GH secretion (-14.45 (8.17)%, p < 0.05 vs control cells). In conclusion, SRPK1 inhibition may represent a novel approach to exert antitumoral effects in somatotroph tumoral cells via SRPK1-SRSF1-VEGF pathway regulation.

Our study reveals a novel lncRNA-mediated signaling axis that integrates transcriptional regulation and splicing reprogramming to sustain cancer stemness and progression in HCC. Targeting this axis offers promising therapeutic opportunities for HCC treatment.

SRPK1 is under-expressed in mucinous CRC, and under-expression is associated with worse OS. This may be due to the positive effects of SRPK1 on oxaliplatin sensitivity.

Our findings suggest that stemness-related heterogeneity in LMS shapes the tumor immune microenvironment and contributes to disease progression. The six identified prognostic markers not only provide insights into the molecular mechanisms of LMS but also represent potential therapeutic targets for personalized treatment.

VEGF splicing in monocytes is regulated differently from VEGF splicing in epithelial or cancer cells suggesting that control of splicing is dependent on cell type and/or environment. SRPK1 inhibition enhances collateralisation in mice, and in human in vitro models of monocyte-dependent impaired angiogenesis.

Additionally, MAGOH knockdown rescued circSRPK1-mediated RONΔ160 formation and GC malignancy. Overall, our research revealed a novel mechanism by which the MAGOH-circSRPK1-hnRNPA2B1-RONΔ160 axis regulated GC cell proliferation and metastasis, broadening the current understanding of circRNA-mediated regulation of tumor progression through aberrant alternative splicing.

However, no clear added efficacy signal was observed of the combination. Trial registration number: NCT04652205 (Nov 29, 2020).