Sox2 inhibits Wnt-β-catenin signaling and metastatic potency of cisplatin-resistant lung adenocarcinoma cells

Abstract

Lung cancer remains one of the most common cancer-associated mortalities worldwide, and platinum-based doublet chemotherapies are recommended as the first-line treatment for advanced non-small cell lung cancer (NSCLC). However, the frequent development of multidrug resistance, to cisplatin regimens in particular, is a major cause of chemotherapy failure in patients with aggressive NSCLC. Wnt/β-catenin signaling and sex-determining region Y box 2 (Sox2) have been implicated in the development and progression and resistance to epidermal growth factor receptor-targeting therapy in lung cancer. The present study aimed to explore the effects of Wnt/β-catenin and Sox2 signaling on the chemoresistance of cisplatin-resistant lung cancer cells by assessing the effects of Sox2 on Wnt/β-catenin signaling activity, cell migration, invasion and clonogenicity, and susceptibility to cisplatin in lung adenocarcinoma A549 cells and cisplatin-resistant A549/DDP cells. The results demonstrated that an enforced expression of Sox2 led to inhibition of Wnt/β-catenin signaling activity, potentially by upregulating glycogen synthase kinase 3 β in A549 and A549/DDP cells. An overexpression of Sox2 promoted cell migration and invasion, in addition to enhancing the clonogenic capacity in A549 cells. Notably, knockdown Sox2 using short hairpin RNA led to an enhanced susceptibility of A549 and A549/DDP cells to cisplatin, along with increased cell apoptosis. The present study thus suggests that Sox2 may be an important regulator in development of chemoresistance of lung cancer cells and may be a novel therapeutic target for treatment chemoresistant lung cancer.

Ibuprofen reduces cell proliferation through inhibiting Wnt/β catenin signaling pathway in gastric cancer stem cells

“…Current study findings were also in accordance with our previous report on effect of ibuprofen on the gene expression of stem cell markers in AGS cell line and the other report about the stemness features of CSCs derived from AGS and MKN-45 cell lines (Mahmoodi and Akrami, 2017). Moreover, other studies demonstrated that SOX2 inhibits gastric cancer as well as lung cancer by suppressing Wnt/b-catenin signaling pathway Sarkar et al, 2016;He et al, 2017). We investigated the effect of ibuprofen on the expression level of some genes which were the downstream of the Wnt signaling pathway or genes that affect the Wnt signaling pathway thus on proliferation, stem cell self-renewal and often cause cancer.…”

“…Current study findings were also in accordance with our previous report on effect of ibuprofen on the gene expression of stem cell markers in AGS cell line (Akrami et al, ) and the other report about the stemness features of CSCs derived from AGS and MKN‐45 cell lines (Mahmoodi and Akrami, ). Moreover, other studies demonstrated that SOX2 inhibits gastric cancer as well as lung cancer by suppressing Wnt/β‐catenin signaling pathway (Chen et al, ; Sarkar et al, ; He et al, ).…”

SOX2 Activation Using CRISPR/dCas9 Promotes Wound Healing in Corneal Endothelial Cells

“…SOX2 has been reported to have a bifunctional activity . SOX2 promotes proliferation and maintains the stemness , whereas it is involved in differentiation in wound healing .…”

Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

“…This is consistent with studies showing that the canonical Wnt/β-catenin pathway plays an important role in cellular migration and invasion in multiple tumor types including breast, prostate, gastric, hepatocellular, lung, and thyroid carcinoma cells. 45–51 Pyrvinium has been shown to inhibit β-catenin driven gene transcription, but multiple different mechanisms can inhibit the Wnt/β-catenin pathway including interruption of Wnt interaction with the Frizzled/LRP receptor, 45,46,50 decreasing Wnt ligands, 49 abrogating β-catenin degradation, 51 or altering β-catenin’s interaction with transcription factors in the nucleus affecting gene transcription. 48 This suggests that drug targeting could be tested at a variety of different points in the Wnt/β-catenin signalling cascade making this a fruitful future direction in cancer therapy, including in WT.…”