LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway

Abstract

Background Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However, the upstream molecules driving the signaling pathways of radiation-induced EMT have not been fully delineated. Methods In this study, RNA-seq-based transcriptome analysis was performed to identify the early responsive genes of HeLa cells to γ-ray irradiation. EMT-associated genes were knocked down by siRNA technology or overexpressed in HeLa cells and A549 cells, and the resulting changes in phenotypes of EMT and radiosensitivity were assessed using qPCR and Western blotting analyses, migration assays, colony-forming ability and apoptosis of flow cytometer assays. Results Through RNA-seq-based transcriptome analysis, we found that LPAR5 is downregulated in the early response of HeLa cells to γ-ray irradiation. Radiation-induced alterations in LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., the early downregulating phase at 2 ~ 4 h and the late upregulating phase at 24 h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers radioresistance to cancer cells. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expression. Conclusions LPAR5 is an important upstream regulator of IR-induced EMT that modulates the ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and identifies promising targets for improving the effectiveness of cancer radiation therapy.

Hypoxia Modulates Radiosensitivity and Response to Different Radiation Qualities in A549 Non-Small Cell Lung Cancer (NSCLC) Cells

“…LPAR5 has recently been reported to be overexpressed in NSCLC [55] and knocking it out in A549 cells has been shown to inhibit apoptosis and oppose growth arrest following irradiation [56]. LPAR5 upregulation, therefore, offers a credible mechanistic justification for increased survival and less pronounced G2 arrest seen after irradiation of A549 cells under hypoxia in our experiments.…”

Irreversible inhibition of estrogen receptor α signaling and the emergence of hormonal resistance in MCF7 breast cancer cells induced by DNA damage agents

“…Additionally, a series of observations underscore the involvement of growth-related pathways, including PI3K/AKT and MAP cascades, in the regulation of ERα activity. Moreover, the role of ERα itself has been implicated in the regulation of cellular radioresistance (58,70,71). Further studies are required for the explanation of the mechanism of the inactivation of ERα by DNA damage agents and how DNA damage inhibits ERα transcription without affecting its expression.…”

Monophosphoryl lipid A ameliorates radiation-induced lung injury by promoting the polarization of macrophages to the M1 phenotype

“…TGF-β1 is a specific cytokine that induces extracellular matrix production [ 39 , 40 ], consistent with our findings. TGF-β promote radiation-induced EMT process [ 41 , 42 ] Nevertheless, the relationship between TLRs and EMT is not well understood. This study revealed that MPLA promotes the polarization of RAW 264.7 cells towards the M1 phenotype and inhibits TGF-β secretion by macrophages.…”