RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer.

Shiming Tan,Min Su,Jiaxin Liang,Pin Yi,Yingrui Shi,Yujuan Zhou,Qianjin Liao,Longzheng Xia,Biao Zeng,Hui Wang,Lu Tang,Jinguan Lin,Yutong Tian,Linda Oyang,Heran Wang,Qing Pan,Shan Rao,Yaqian Han

doi:10.3389/fonc.2020.00649

Abstract

Radiation therapy is a common and acceptable approach for lung cancer. Although the benefit of ionizing radiation (IR) is well-established, cancer cells can still survive via pro-survival and metastasis signaling pathways. Ras related C3 botulinum toxin substrate1 (RAC1), a member of Rho family GTPases, plays important roles in cell migration and survival. In the present study, we investigated the effects of RAC1 on the survival of lung cancer cells treated with irradiation. The results showed RAC1 is overexpressed in lung cancer cells and promoted cell proliferation and survival. Furthermore, IR induced RAC1 expression and activity via the activation of PI3K/AKT signaling pathway, and then enhancing cell proliferation, survival, migration and metastasis and increasing levels of epithelial-to-mesenchymal transition (EMT) markers, which facilitated the cell survival and invasive phenotypes. In addition, overexpression of RAC1 attenuated the efficacy of irradiation, while inhibition of RAC1 enhanced sensitivity of irradiation in xenograft tumors in vivo. Collectively, we further found that RAC1 enhanced radioresistance by promoting EMT via targeting the PAK1-LIMK1-Cofilins signaling in lung cancer. Our finding provides the evidences to explore RAC1 as a therapeutic target for radioresistant lung cancer cells.

Highlights

Lung cancer is the most common cancer and one of the leading causes of death worldwide [1]
Our previous study have been elucidated that related C3 botulinum toxin substrate1 (RAC1) expression is correlated with the expression of epithelial-to-mesenchymal transition (EMT) markers in non-small cell lung cancer (NSCLC) [38]
The results showed that RAC1 expression was elevated in four NSCLC cell lines relative to normal lung HBE epithelial cells (Figures S1A,B)

Summary

Introduction

Lung cancer is the most common cancer and one of the leading causes of death worldwide [1]. Increasing evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) mediated tumor metastasis is closely associated with radiation resistance [8, 9]. The biological process during EMT endows epithelial cells lose their apical-basal polarity and acquire mesenchymal cell traits [10, 11], which is characterized by the loss of epithelial morphology and the acquisition of mesenchymal morphology, of which the epithelial markers includes E-cadherin, Desmoplakin, Occludins, Claudins, and ZO-1) and RAC1 Regulates Lung Cancer Radioresistance mesenchymalmarkers includs N-cadherin, vimentin, and FSP1. Many radioresistant cancer cells demonstrate EMT is considered to link to adaptation to hypoxia [15], enhanced DNA repair capacity [10, 15, 16], activated molecular events, and signaling pathways [17]

Methods

Results

Conclusion