Overexpression of Wnt7a enhances radiosensitivity of non-small-cell lung cancer via the Wnt/JNK pathway.

Zhixia Wei,Xianhua Xu,Shijie Xu,Pingping Ai,Shun Tan,Junzhe Li

doi:10.1242/bio.050575

Abstract

ABSTRACTThe Wingless-type protein 7a (Wnt7a) plays an antiproliferative role in non-small-cell lung cancer (NSCLC). Previous studies have indicated that Wnt7a expression was downregulated in radiation-resistant NSCLC cells. However, little is known about its biological functions and molecular mechanisms in radiosensitivity of NSCLC. Thus, NSCLC cell proliferation and apoptosis in response to Wnt7a overexpression and/or radiation were determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyl-tertazolium bromide (MTT) assay and flow cytometry, respectively. The activation of the Wnt/cJun N-terminal kinase (JNK) and Wnt/β-catenin signaling pathways were further examined by western blot in NSCLC cell lines H1650 and A549. Wnt7a overexpression combined with radiation-inhibited cell proliferation and induced apoptosis in NSCLC cell lines compared to Wnt7a overexpression or radiotherapy alone. In addition, the phosphorylation of JNK, but not β-catenin, was congruent with the changes in Wnt7a overexpression and/or radiation. Moreover, the Wnt/JNK pathway could induce the apoptosis of NSCLC cells through the mitochondrial pathway. Inhibition of the Wnt/JNK signaling pathway by SP600125, a JNK inhibitor, contributed to proliferation induction in NSCLC cells. Taken together, these results showed that Wnt7a overexpression sensitized NSCLC cell lines to radiotherapy through the Wnt/JNK signaling pathway.

Highlights

Lung cancer is the leading cause of cancer mortality in the world, with non-small-cell lung cancer (NSCLC) accounting for up to 80% of total pulmonary malignancies (Jemal et al, 2011)
Wingless-type protein 7a (Wnt7a) overexpression enhanced the inhibition of NSCLC cell proliferation to irradiation To investigate the effects of Wnt7a overexpression on radiationinduced anti-tumor therapy in NSCLC cell lines H1650 and A549, the MTT assay was used to determine the proliferation of cells transfected with pcDNA6-Wnt7a or empty vector control combined with radiation or radiation alone
Overexpression of Wnt7a (60.2% in H1650, 59.8% in A549) displayed lower proliferation rates compared with cells with empty vector control (23.9% in H1650, 21.8% in A549), and empty vector control had no significant effect on the cell proliferation compared with radiation alone

Summary

Introduction

Lung cancer is the leading cause of cancer mortality in the world, with non-small-cell lung cancer (NSCLC) accounting for up to 80% of total pulmonary malignancies (Jemal et al, 2011). Radiotherapy is the commonly used treatment for localized lung cancer, and it has the. Received 5 January 2020; Accepted 1 May 2020 advantage of being non-invasive and well tolerated (Harris et al, 2014; Kim et al, 2017). Radiotherapy plays a crucial role for the local treatment of NSCLC patients including DNA damage, triggering cell cycle arrest, and apoptosis (Palayoor et al, 1995; Ning and Knox, 1999). Radio-resistance is one major obstacle in the success of radiation treatment. Novel therapeutic strategies to improve the effectiveness of radiation treatment on NSCLC are urgently needed

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