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

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 spl...

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Autores principales:	Simon Uzor, Sean R. Porazinski, Ling Li, Bethany Clark, Masahiko Ajiro, Kei Iida, Masatoshi Hagiwara, Abdullah A. Alqasem, Claire M. Perks, Ian D. Wilson, Sebastian Oltean, Michael R. Ladomery
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1595aa359a334c009f784001b7ba6977
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spelling	oai:doaj.org-article:1595aa359a334c009f784001b7ba69772021-12-02T15:51:16ZCDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer10.1038/s41598-021-86908-62045-2322https://doaj.org/article/1595aa359a334c009f784001b7ba69772021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86908-6https://doaj.org/toc/2045-2322Abstract 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. TG003 reduced cell proliferation and increased apoptosis in PC3 and DU145 cells. Conversely, the overexpression of CLK1 in PC3 cells prevented TG003 from reducing cell proliferation. TG003 slowed scratch closure and reduced cell migration and invasion in a transwell assay. TG003 decisively inhibited the growth of a PC3 cell line xenograft in nude mice. We 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.Simon UzorSean R. PorazinskiLing LiBethany ClarkMasahiko AjiroKei IidaMasatoshi HagiwaraAbdullah A. AlqasemClaire M. PerksIan D. WilsonSebastian OlteanMichael R. LadomeryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Simon Uzor Sean R. Porazinski Ling Li Bethany Clark Masahiko Ajiro Kei Iida Masatoshi Hagiwara Abdullah A. Alqasem Claire M. Perks Ian D. Wilson Sebastian Oltean Michael R. Ladomery CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
description	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. TG003 reduced cell proliferation and increased apoptosis in PC3 and DU145 cells. Conversely, the overexpression of CLK1 in PC3 cells prevented TG003 from reducing cell proliferation. TG003 slowed scratch closure and reduced cell migration and invasion in a transwell assay. TG003 decisively inhibited the growth of a PC3 cell line xenograft in nude mice. We 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.
format	article
author	Simon Uzor Sean R. Porazinski Ling Li Bethany Clark Masahiko Ajiro Kei Iida Masatoshi Hagiwara Abdullah A. Alqasem Claire M. Perks Ian D. Wilson Sebastian Oltean Michael R. Ladomery
author_facet	Simon Uzor Sean R. Porazinski Ling Li Bethany Clark Masahiko Ajiro Kei Iida Masatoshi Hagiwara Abdullah A. Alqasem Claire M. Perks Ian D. Wilson Sebastian Oltean Michael R. Ladomery
author_sort	Simon Uzor
title	CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
title_short	CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
title_full	CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
title_fullStr	CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
title_full_unstemmed	CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
title_sort	cdc2-like (clk) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1595aa359a334c009f784001b7ba6977
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CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer

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