MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability

Abstract

Background Head and neck squamous-cell carcinoma (HNSCC) ranks sixth among cancers worldwide. Though several molecular mechanisms of tumor initiation and progression of HNSCC are known, others remain unclear. Significance of p38/MAPKAPK2 (Mitogen-activated protein kinase-activated protein kinase-2) pathway in cell stress and inflammation is well established and its role in tumor development is being widely studied. Methods We have elucidated the role of MAPKAPK2 (MK2) in HNSCC pathogenesis using clinical tissue samples, MK2-knockdown (MK2 KD ) cells and heterotropic xenograft mice model. Results In patient-derived tissue samples, we observed that MK2 is reproducibly overexpressed. Increased stability of cyclin-dependent kinase inhibitor 1B (p27), mitogen-activated protein kinase phosphatase-1 (MKP-1) transcripts and decreased half-life of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) transcripts in MK2 KD cells suggests that MK2 regulates their transcript stability. In vivo xenograft experiments established that knockdown of MK2 attenuates course of tumor progression in immunocompromised mice. Conclusion Altogether, MK2 is responsible for regulating the transcript stability and is functionally important to modulate HNSCC pathogenesis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1167-2) contains supplementary material, which is available to authorized users.

Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2

“…To solve this problem and effectively inhibit p38MAPK, researchers turned their focus to many of its downstream targets, such as MAPKAPK2. Previous studies have shown that targeting MAPKAPK2 to interdict its downstream events is as good as direct upstream inhibition of the p38MAPK pathway without obvious side effects of p38MAPK inhibitors (38)(39)(40). In the present study, we have demonstrated a direct binding between MAPKAPK2 and Sophoridine by DARTS assay and CETSA.…”

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

“…HNSCC is the sixth leading cancer by incidence worldwide and the eighth most common cause of cancer death [ 9 , 10 ]. Although in the past two decades new surgical and medical treatments have improved patients’ quality of life, the 5-year survival remains 40–50% of patients [ 11 ].…”

Atypical p38 Signaling, Activation, and Implications for Disease

“…Phosphorylated MK2 and MK3 can then further activate other substrates such as cyclic AMP-responsive element binding protein (CREB) [ 40 ] and heat shock protein 27 (HSP27) to regulate actin filament remodeling [ 41 ]. MK2 is also an important regulator of post-transcriptional regulation of gene expression through modulation of adenylate-uridylate-rich elements (ARE)-binding proteins tristetraprolin (TTP) and HuR (reviewed here [ 42 ]). However, mitogen- and stress-activated kinase 1 and 2 (MSK1 and MSK2) translocate to the nucleus to mediate activation of nucleosome components and transcription factors [ 43 ].…”

“…However, the story is complicated by a dichotomy of responses where p38 can exert both pro- and anti-inflammatory effect during disease progression. P38 can directly phosphorylate pro-inflammatory transcription factors such as MEF2C [ 168 ], and indirectly regulate inflammatory cytokine production through the MK2/3-TTP axis, where p38 phosphorylation of TTP prevents TTP-dependent degradation of AU-rich cytokine mRNA, leading to an accelerated inflammatory response [ 39 , 42 , 132 ]. As such p38 is an essential driver of inflammatory mediators such as COX2, MMP9, iNOS, TNFα, and IL6 [ 36 , 169 , 170 , 171 , 172 ].…”