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

Abstract

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). RNAseq 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 posttranscriptional aberration could be a therapeutic target.

Post-transcriptional regulation of BIRC5/survivin expression and induction of apoptosis in breast cancer cells by tristetraprolin

“…On the other hand, TTP dysregulation in cancer has been attributed to a variety of mechanisms. One is its phosphorylation by several kinases such as ERK2 [ 57 ], p38 MAPK [ 58 ], JNK [ 59 ], MK2 [ 60 ] and PLK1 [ 61 ] leading to increased stability and, at the same time, reduced destabilizing activity [ 62 , [ 63 ]. Kinase activity is upregulated in tumours making kinases important targets for cancer treatment [ 64 , [ 65 ].…”

“…Kinase activity is upregulated in tumours making kinases important targets for cancer treatment [ 64 , [ 65 ]. Indeed, inhibition of PLK1 using volasertib resulted in decreased TTP phosphorylation, decreased stability of the protein, and subsequently reduced tumour growth in mice [ 61 ]. Further elucidation of the role of PLK1 inhibition on BIRC5 expression and apoptosis in cancer cell lines may provide useful information on enhancing TTP regulation of BIRC5 and other ARE-cancer gene targets.…”

Differential upregulation of AU-rich element-containing mRNAs in COVID-19

“…Several cellular signaling pathways induce ARE-containing mRNAs at the transcriptional level such as NF-kB, AP1, interferon, IL-6/ JAK/STAT, MAPK kinases, Hippo, PI3K and others [23][24][25][26]. The same mRNAs can be regulated at the post-transcriptional level by the same and/or additional signaling pathways like p38 MAPK, PI3K, ERK, PLK1, PKC and other [14,27,28]. AREs are not involved in the regulation of transcription, but they are located in most mRNAs that are induced during inflammation at the transcriptional level.…”

Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential

“…PLK1 leads to the phosphorylation of zinc finger protein-36/tristetraprolin (ZFP36/TTP) and interacts with mitogen-activated protein kinase-activated protein kinase-2 (MK2) and possibly bidirectionally phosphorylates it. The PLK1-MK2-TPP pathway regulates inflammatory responses . A PLK1-specific siRNA combined with paclitaxel or herceptin in the treatment of breast cancer activated the caspase pathway and thus increased the sensitivity of breast cancer cells to chemotherapy drugs. , (vi).…”

“…The PLK1-MK2-TPP pathway regulates inflammatory responses. 83 A PLK1-specific siRNA combined with paclitaxel or herceptin in the treatment of breast cancer activated the caspase pathway and thus increased the sensitivity of breast cancer cells to chemotherapy drugs. 82,84 (vi).…”