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

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 facto...

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Vydáno v:	Scientific reports Ročník 11; číslo 1; s. 7963 - 12
Hlavní autoři:	Uzor, Simon, Porazinski, Sean R., Li, Ling, Clark, Bethany, Ajiro, Masahiko, Iida, Kei, Hagiwara, Masatoshi, Alqasem, Abdullah A., Perks, Claire M., Wilson, Ian D., Oltean, Sebastian, Ladomery, Michael R.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 12.04.2021 Nature Publishing Group Nature Portfolio
Témata:	631/337/1645/1792 631/337/1645/1946 631/67/589/466 Alternative splicing Alternative Splicing - genetics Animals Apoptosis Apoptosis - drug effects Benzothiazole Benzothiazoles - pharmacology Cdc2 protein Cell growth Cell Line, Tumor Cell migration Cell Movement - drug effects Cell proliferation Cell Proliferation - drug effects Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - chemistry Cyclin-Dependent Kinases - genetics Cyclin-Dependent Kinases - metabolism Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Humanities and Social Sciences Humans Kinases Male Mice Mice, Nude Molecular Targeted Therapy multidisciplinary Neoplasm Invasiveness Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Protein kinase Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use RNA-Seq Science Science (multidisciplinary) Thiazoles - pharmacology Tumor cell lines Xenograft Model Antitumor Assays Xenografts
ISSN:	2045-2322, 2045-2322
On-line přístup:	Získat plný text
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-021-86908-6