CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer

Simon Uzor, Sean Porazinski, Ling Li, Bethany Clark, Masahiko Ajiro, Kei lida, Masatoshi Hagiwara, Abdullah I M Alqasem, Claire M Perks, Ian Wilson, Sebastian Oltean*, Michael R. Ladomery

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Dysregulation of alternative splicing is a feature of cancer, both in aetiology and progression. It occurs because of mutations in splice sites or sites that regulate splicing, or because of the altered expression and activity of splice factors and of splice factor kinases that regulate splice factor activity. Recently the CDC2-like kinases (CLKs) have attracted attention due to their increasing involvement in cancer. We measured the effect of the CLK inhibitor, the benzothiazole TG003, on two prostate cancer cell lines. We find that TG003 drastically reduced cell proliferation and increased apoptosis in PC3 and DU145 cells; the same was observed when when CLK1 was knocked-down by RNA interference. Conversely, the overexpression of CLK1 in PC3 cells prevented TG003 from reducing cell proliferation. TG003 also slowed gap closure in a scratch assay; reduced cell migration and invasion in a transwell assay; and increased E-cadherin while reducing vimentin expression. TG003 strongly inhibited the growth of a PC3 cell line xenograft in nude mice. We also performed a transcriptomic analysis of cells treated with TG003. We report widespread and consistent changes in alternative splicing of cancer-associated genes including CENPE, ESCO2, CKAP2, MELK, ASPH and CD164 in both HeLa and PC3 cells. Together these findings suggest that targeting CLKs will provide novel therapeutic opportunities in prostate cancer.
Original languageEnglish
Article number7963 (2021)
Number of pages12
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 12 Apr 2021

Keywords

  • Alternative splicing
  • Prostate cancer
  • RNA splicing

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