Nobiletin Inhibits Non-Small-Cell Lung Cancer by Inactivating WNT/β-Catenin Signaling through Downregulating miR-15-5p

Abstract

Background. Nobiletin is a natural compound with anticancer activity; however, the mechanism is not clear. Methods. The inhibitory effect of nobiletin on non-small-cell lung cancer (NSCLC) cells was examined using soft agar, Transwell, and apoptosis analyses. Cancer stemness was measured by sphere assay. Genes and miRNAs regulated by nobiletin were identified by whole-genome sequencing. Protein levels were detected by western blot and immunofluorescence assays. Results. Nobiletin significantly inhibited NSCLC cell colony formation and sphere formation and induced apoptosis. Nobiletin upregulated negative regulators of WNT/β-catenin signaling, including NKD1, AXIN2, and WIF1, while it inhibited the expression of β-catenin and its downstream genes, including c-Myc, c-Jun, and cyclin D1. Furthermore, we identified that GN inhibits miR-15-5p expression in NSCLC cells and that NKD1, AXIN2, and WIF1 are the target genes of miR-15-5p. Conclusions. Nobiletin has a strong inhibitory effect on NSCLC, and nobiletin plays an anticancer role by inhibiting miR-15-5p/β-catenin signaling in NSCLC.

miR‑29a‑3p inhibits the malignant characteristics of non‑small cell lung cancer cells by reducing the activity of the Wnt/β‑catenin signaling pathway

“…LiCl partially reversed the decrease in cell proliferation, invasion, and migration induced by miR-29a-3p overexpression. This results is in agreement with previous studies which showed that activation of Wnt/β-catenin signaling facilitates tumor growth in lung cancer ( 40 ). The results showed that miR-29a-3p had a tumor suppressive role in NSCLC by restraining Wnt/β-catenin signaling.…”

“…To further investigate the underlying mechanisms involved, the association between miR-29a-3p and Wnt/β-catenin signaling pathway in NSCLC was further examined next. The Wnt/β-catenin signaling pathway is required for numerous core biological processes, whilst also driving tumor initiation and progression ( 40 ). Wnt3a and β-catenin are Wnt signaling pathway-related proteins, that can enter the nucleus to regulate gene transcription.…”

Multifunctional role of Nobiletin in cancer chemoprevention

“…Remarkably, overexpression of miRNA-15-5p abrogated nobiletin-mediated repression of β-catenin. These findings indicated that nobiletin inhibited WNT/βcatenin pathway mainly by downregulation of miRNA-15-5p in NSCLC (87).…”

Cell cycle associated miRNAs as target and therapeutics in lung cancer treatment

“…Adriamycin is another drug that is listed which NSCLC has been found sensitized to when mimicking miR-138 [ 210 ]. As for picking antagomiRs, anti-miR-205, anti-miR-223 and anti-miR-15-5p resulted in sensitization of NSCLC to Cisplatin [ 211 ], Doxorubicin and Cisplatin [ 212 , 213 ] and Nobiletin [ 214 ], respectively. However, anti-miR-138-5p rather showed desensitization of NSCLC to Cisplatin implying that overexpression of miR-138-5p would retain chemosensitivity in NSCLC against the Platinum drug [ 215 ].…”