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

Abstract Epithelial-to-mesenchymal transition (EMT) is a critical event contributing cancer cells more aggressive phenotypes. EMT programs are frequently activated in radiation-targeted cells during the course of radiotherapy, and which often endows cancers the acquired radioresistance. Through RNA-seq based transcriptome analysis, here we found that LPAR5 is downregulated in the early response of HeLa cells to γ-rays irradiation. Radiation-induced alterations of LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., early downregulating phase at 2 ~ 4h and late upregulating phase at 24h 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 cancer cells radioresistance. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expressions. In conclusion, LPAR5 is an important upstream regulator of IR-induced EMT through modulating ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and promising target for improving the effectiveness of cancer radiation therapy.