SRPK1 is a determinant of chemoresistance to Docetaxel in prostate cancer

Authors

Duzgun, D., Read, W., Oltean, S.

Abstract

Docetaxel is a major therapeutic option for advanced prostate cancer, but the development of acquired resistance substantially limits its clinical efficacy. Although multiple mechanisms have been implicated in docetaxel resistance, the upstream regulatory pathways coordinating these phenotypes remain incompletely understood. Here, we investigated the role of serine/arginine-rich protein kinase 1 (SRPK1), a key regulator of pre-mRNA splicing, in acquired docetaxel resistance in prostate cancer. Docetaxel-resistant PC3 cells showed increased SRPK1 expression at both the protein and RNA levels. Genetic depletion or pharmacological inhibition of SRPK1 substantially restored docetaxel sensitivity, whereas ectopic SRPK1 expression in parental PC3 cells increased resistance. Mechanistically, SRPK1 inhibition reduced expression of {beta}III-tubulin and restored docetaxel-induced microtubule bundling. SRPK1 inhibition also increased apoptosis in resistant cells, accompanied by increased cleavage of caspase-8, caspase-9 and PARP. In parallel, SRPK1 inhibition restored E-cadherin expression and reduced the enhanced migratory phenotype of resistant cells. At the signalling and RNA-processing levels, docetaxel-resistant cells exhibited increased EGFR expression and increased phosphorylation of the SRPK1 substrate SRSF1. SRSF1 depletion partially restored docetaxel sensitivity, supporting an EGFR-SRPK1-SRSF1 pathway in resistance. Importantly, inhibition of SRPK1 or depletion of SRSF1 altered the splicing of apoptosis- and microtubule-associated genes, increasing the pro-apoptotic Bcl-xS and MCL-1S isoforms and shifting tau splicing towards 3R at the expense of 4R. Collectively, these findings identify SRPK1 as a central regulator of multiple phenotypic and molecular features of docetaxel resistance in prostate cancer. Targeting SRPK1-dependent splicing may therefore represent a strategy to re-sensitize resistant prostate cancer cells to docetaxel.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 18 Sep 2026.

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