Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway.

Jiali Yang,Xiaoming Liu,Kangjian Zhang,Jing Li,Jing Xue,Juan Chen,Jun Wei,Juan Shi,Yongzhao Zhu,Jing Wu,Jinxi He

doi:10.1155/2016/1690896

Jiali Yang, Xiaoming Liu + Show 9 more

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https://doi.org/10.1155/2016/1690896

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Abstract

The development of chemoresistance to cisplatin regimens causes a poor prognosis in patients with advanced NSCLC. The role of noncanonical Wnt signaling in the regulation of properties of lung cancer stem cells and chemoresistance was interrogated, by accessing capacities of cell proliferation, migration, invasion, and clonogenicity as well as the apoptosis in A549 cell lines and cisplatin-resistant A549 cells treated with Wnt5a conditional medium or protein kinase C (PKC) inhibitor GF109203X. Results showed that the noncanonical Wnt signaling ligand, Wnt5a, could promote the proliferation, migration, invasion, and colony formation in A549 lung adenocarcinoma cells and cisplatin-resistant A549/DDP cells and increase the fraction of ALDH-positive cell in A549/DDP cells. An exposure of cells to Wnt5a led to a significant reduction of A549/DDP cell apoptosis but not A549 cells. An addition of GF109203X could both strikingly increase the baseline apoptosis and resensitize the Wnt5a-inhibited cell apoptosis. Interestingly, an inhibition of Wnt/PKC signaling pathway could reduce properties of lung cancer stem cells, promote cell apoptosis, and resensitize cisplatin-resistant cells to cisplatin via a caspase/AIF-dependent pathway. These data thus suggested that the Wnt5a could promote lung cancer cell mobility and cisplatin-resistance through a Wnt/PKC signaling pathway and a blockage of this signaling may be an alternative therapeutic strategy for NSCLC patients with resistance to chemotherapies.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide [1], of which the non-small-cell lung cancer (NSCLC) accounts for more than 80–85% of all patients with lung cancers [2, 3]
In order to access the potential impact of Wnt5a on metastatic properties of lung cancer cells, its effects on the proliferation, migration, and invasion in lung adenocarcinoma A549 cells and cisplatin-resistant A549/DDP cells were examined in terms of Cell Counting Kit (CCK) assay for cell viability, scratch healing assay for cell migration, and transwell assay for cell invasion
Wnt5a was transcribed based on multiple mechanisms, including Notch, Hedgehog, TGFβ, and NF-κB signaling cascades [62]. In agreement with these findings, our results suggested that a Wnt5a/protein kinase C (PKC)-mediated caspase-dependent apoptosis signaling pathway and the NF-κB signaling cascade were involved in the metastatic potentials, stemness, and chemoresistance in A549 and cisplatin-resistant A549/DDP NSCLC cells

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide [1], of which the non-small-cell lung cancer (NSCLC) accounts for more than 80–85% of all patients with lung cancers [2, 3]. Despite huge progresses that have been made in treatments of this disease during last two decades, the prognosis and a five-year survival rate for patients with aggressive NSCLC remain poor [4, 5]. Cisplatin-based chemotherapy is the first-line therapy for advanced NSCLC, which is based on the formation of cisplatin-DNA that leads to DNA damage and sequentially activates apoptosis signaling pathways in cells [6]. The development of resistance to cisplatin leads to failure and poor prognosis in NSCLC patients treated with chemotherapy regimens. The mechanisms underlying chemoresistances are currently not fully understood; it is a need to elucidate the molecular mechanism underpinning the cisplatinresistance in order to develop effective therapeutic agents and/or strategies for NSCLC treatments.

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