Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

Abstract

Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF-κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N-cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR-200, miR-303, miR-302, miR-199 and miR-328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.

Procyanidin B2 inhibits high glucose-induced epithelial-mesenchymal transition in HK-2 human renal proximal tubular epithelial cells

“…The transforming growth factor (TGF)-β/small mothers against decapentaplegic (Smad) and mitogen-activated protein kinase (MAPK)/P38 signaling pathways are involved in promoting EMT and are associated with the development of DN (10,11). The aim of the present study was to determine the role of the MAPK/P38 and TGF-β/Smad signaling pathways in HG-induced EMT, and to examine the changes in the two pathways in HK-2 cells cultured with procyanidin B2.…”

SiRNA-HMGA2 weakened AGEs-induced epithelial-to-mesenchymal transition in tubular epithelial cells

“…The ROS/p38-MAPK signaling pathway has been reported to be involved in EMT in the different cells [12,13]. Having shown that SiRNA-HMGA2 inhibited EMT, we next explored the effect of SiRNA-HMGA2 on ROS/P38-MAPK signaling pathway in NRK-52E cells.…”

miR141 expression is downregulated and negatively correlated with STAT5 expression in esophageal squamous cell carcinoma

“…STAT5, an important signal transducer and transcription activator, has an important role in the Janus kinase/STAT signaling pathway (8). Its expression level has been shown to be significantly increased in tumors, where it is directly involved in differentiation, invasion, proliferation and apoptosis (9)(10)(11).…”