Kinome inhibition reveals a role for polo‐like kinase 1 in targeting post‐transcriptional control in cancer

Autor: Ayodele Alaiya, Norah Al-Souhibani, Latifa Al-Haj, Qamraa H. Al‐Qahtani, Falah Al-Mohanna, Edward Hitti, Suhad Al-Yahya, Walid Moghrabi, Maher Al-Saif, Khalid S.A. Khabar, Linah Mahmoud
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Mice
Nude
Cell Cycle Proteins
Protein Serine-Threonine Kinases
PLK1
03 medical and health sciences
Mice
0302 clinical medicine
breast cancer
Tristetraprolin
mRNA decay
Neoplasms
Proto-Oncogene Proteins
Genetics
ZFP36
Animals
Humans
kinase inhibitors
Kinome
post‐transcriptional control
Phosphorylation
RNA Processing
Post-Transcriptional
3' Untranslated Regions
Protein Kinase Inhibitors
Research Articles
RC254-282
AU-rich element
Kinase
Chemistry
Pteridines
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
General Medicine
targeted therapy
Xenograft Model Antitumor Assays
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Molecular Medicine
Ectopic expression
Protein Kinases
AU‐rich elements
Research Article
Zdroj: Molecular Oncology, Vol 15, Iss 8, Pp 2120-2139 (2021)
Molecular Oncology
ISSN: 1574-7891
1878-0261
Popis: Dysfunctions in post‐transcriptional control are observed in cancer and chronic inflammatory diseases. Here, we employed a kinome inhibitor library (n = 378) in a reporter system selective for 3′‐untranslated region–AU‐rich elements (ARE). Fifteen inhibitors reduced the ARE‐reporter activity; among the targets is the polo‐like kinase 1 (PLK1). RNA‐seq experiments demonstrated that the PLK1 inhibitor, volasertib, reduces the expression of cytokine and cell growth ARE mRNAs. PLK1 inhibition caused accelerated mRNA decay in cancer cells and was associated with reduced phosphorylation and stability of the mRNA decay‐promoting protein, tristetraprolin (ZFP36/TTP). Ectopic expression of PLK1 increased abundance and stability of high molecular weight of ZFP36/TTP likely of the phosphorylated form. PLK1 effect was associated with the MAPK‐MK2 pathway, a major regulator of ARE‐mRNA stability, as evident from MK2 inhibition, in vitro phosphorylation, and knockout experiments. Mutational analysis demonstrates that TTP serine 186 is a target for PLK1 effect. Treatment of mice with the PLK1 inhibitor reduced both ZFP36/TTP phosphorylation in xenograft tumor tissues, and the tumor size. In cancer patients' tissues, PLK1/ARE‐regulated gene cluster was overexpressed in solid tumors and associated with poor survival. The data showed that PLK1‐mediated post‐transcriptional aberration could be a therapeutic target.
A kinome inhibitor screen identified several kinases operating in post‐transcriptional control. Among those is polo‐like kinase 1 (PLK1), which is overexpressed in cancer, leading to MAPK‐activated protein kinases 2 (MK2)‐dependent phosphorylation and inactivation of the mRNA decay‐promoting protein, tristetraprolin. These events cause overexpression of many cancer genes; thus, therapeutic targeting of PLK1 kinase may restore post‐transcriptional defects in disease.
Databáze: OpenAIRE
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