Euphorbiasteroid Abrogates EGFR and Wnt/β-Catenin Signaling in Non-Small-Cell Lung Cancer Cells to Impart Anticancer Activity

Abstract

EGFR and Wnt/β-catenin signaling pathways play a prominent role in tumor progression in various human cancers including non-small-cell lung carcinoma (NSCLC). Transactivation and crosstalk between the EGFR and Wnt/β-catenin pathways may contribute to the aggressiveness of cancers. Targeting these oncogenic pathways with small molecules is an attractive approach to counteract various types of cancers. In this study, we demonstrate the effect of euphorbiasteroid (EPBS) on the EGFR and Wnt/β-catenin pathways in NSCLC cells. EPBS induced preferential cytotoxicity toward A549 (wildtype EGFR-expressing) cells over PC-9 (mutant EGFR-expressing) cells. EPBS suppressed the expression of EGFR, Wnt3a, β-catenin, and FZD-1, and the reduction in β-catenin levels was found to be mediated through the activation of GSK-3β. EPBS reduced the phosphorylation of GSK-3βS9 with a parallel increase in β-TrCP and phosphorylation of GSK-3βY216. Lithium chloride treatment increased the phosphorylation of GSK-3βS9 and nuclear localization of β-catenin, whereas EPBS reverted these effects. Forced expression or depletion of EGFR in NSCLC cells increased or decreased the levels of Wnt3a, β-catenin, and FZD-1, respectively. Overall, EPBS abrogates EGFR and Wnt/β-catenin pathways to impart its anticancer activity in NSCLC cells.

2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells

“…To find out the effect of TMP on cell invasion, we performed an invasion assay using the Boyden chamber as reported previously [ 33 ].…”

Cannabidiol activates MAPK pathway to induce apoptosis, paraptosis, and autophagy in colorectal cancer cells

“…Lowering of Alix expression, elevation in the expression of cleavage of PARP, and reduction of LC3 levels are the markers of paraptosis, apoptosis, and autophagy, respectively. 31,35,37,38 CBD induced the dose-dependent cleavage of PARP and expression of LC3 as well as suppressed the expression of Alix in HT-29, SW480, HCT-116 and HCT-15 cells (Figure 1C). These results suggested that CBD imparts cytotoxicity by inducing apoptosis, paraptosis, and autophagy.…”

Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response

“…The activation of Wnt signaling results in the nuclear translocation of β-catenin followed by the expression of genes associated with cell growth and EMT. [294][295][296][297] The activation of Wnt signaling has been reported to play an important role in pancreatic cancer carcinogenesis and metastasis. 298 Furthermore, Wnt signaling is positively associated with drug resistance of these tumor cells and its inhibition can reverse EMT.…”

“…Understanding of miRNA/STAT3 axis and their crosstalk with other related molecular pathways can pave the way to the treatment of this malignant condition and the development of novel therapeutics. The activation of Wnt signaling results in the nuclear translocation of β‐catenin followed by the expression of genes associated with cell growth and EMT 294–297 . The activation of Wnt signaling has been reported to play an important role in pancreatic cancer carcinogenesis and metastasis 298 .…”