Genistein inhibits lung cancer cell stem‑like characteristics by modulating MnSOD and FoxM1 expression

Abstract

Manganese superoxide dismutase (MnSOD) promotes invasive and migratory activities by upregulating Forkhead box protein M1 (FoxM1) expression. The present study investigated whether modulation of MnSOD and FoxM1 expression was responsible for the antitumor effects of genistein on cancer stem-like cells (CSLCs) derived from non-small cell lung cancer cells (NSCLCs). Spheroids prepared from H460 or A549 cells were defined as lung cancer stem-like cells (LCSLCs) and were treated with genistein. The Cell Counting Kit-8 assay was performed to assess human lung fibroblast IMR-90 cell proliferation, as well as NSCLC H460 and A549 cell proliferation following treatment with genistein. MnSOD, FoxM1, cluster of differentiation (CD)133, CD44, BMI1 proto-oncogene, polycomb ring finger (Bmi1) and Nanog homeobox (Nanog) protein expression levels were examined via western blotting. The sphere formation assay was conducted to evaluate LCSLC self-renewal potential, and LSCLC migratory and invasive activities were analyzed using the wound healing and Transwell invasion assays, respectively. Knockdown and overexpression of MnSOD and FOXM1 via short hairpin-RNA or cDNA transfection were performed. The results indicated that genistein (80 and 100 µM) suppressed H460 and A549 cell viability compared with IMR-90 cells. Sub-cytotoxic concentrations of genistein (20 and 40 µM) inhibited sphere formation activity and decreased the protein expression levels of CD133, CD44, Bmi1 and Nanog in LCSLCs compared with the control group. Genistein also suppressed the migratory and invasive activities of LCSLCs compared with the control group. MnSOD and FoxM1 overexpression antagonized the effects of genistein (40 µM), whereas MnSOD and FoxM1 knockdown enhanced the inhibitory effects of genistein (20 µM) on CSLC characteristics of LCSLCs. Overall, the results suggested that genistein suppressed lung cancer cell CSLC characteristics by modulating MnSOD and FoxM1 expression levels.

Soy isoflavone genistein inhibits hsa_circ_0031250/miR‐873‐5p/FOXM1 axis to suppress non‐small‐cell lung cancer progression

“…Additionally, previous studies reported that genistein could induce cell cycle arrest and apoptosis in NSCLC cells 36,37 . Moreover, genistein could repress the stem‐like characteristics in NSCLC cells 26 . These studies implied the anti‐tumor function of genistein in NSCLC.…”

“…36,37 Moreover, genistein could repress the stem-like characteristics in NSCLC cells. 26 These studies implied the anti-tumor function of genistein in NSCLC. Similarly, we also found the inhibitive function of genistein in NSCLC progression via inhibiting cell growth and metastasis.…”

“…Similarly, our study also found this function, and identified that miR‐873‐5p constrained NSCLC cell progression under genistein exposure by decreasing FOXM1. A previous study suggested that genistein could decrease FOXM1 expression, 26 while it was unknown how genistein controlled FOXM1. Here we found that genistein could regulate circ_0031250/miR‐873‐5p axis to reduce FOXM1 expression in NSCLC cells.…”

“…Forkhead box M1 (FOXM1) is an important oncogene in various cancers, including NSCLC 24,25 . More importantly, this protein can respond to genistein exposure to control the stem‐like characteristics of NSCLC cells 26 . The bioinformatics analysis used CircInteractome and TargetScan to analyze the potential interaction of circ_0031250/miR‐873‐5p/FOXM1 axis, while this network has not been reported.…”

A narrative review of the migration and invasion features of non-small cell lung cancer cells upon xenobiotic exposure: insights from in vitro studies

“…Genistein, a flavonoid from soy, was able to suppress migration and invasion of lung cancer stem-like cells (LCSLCs) derived from NSCLC cells by regulating the expression of manganese superoxide dismutase (MnSOD) and Forkhead box protein M1 (FoxM1) (87). Hesperidin can be extracted from citrus fruits and a study proposed that its inhibitory properties on migration and invasion occur via mediation of the SDF-1/CXCR-4 signaling cascade by reducing the secretion of stromal cell-derived factor 1 (SDF-1), resulting in a decrease in CXCR-4, p-p65, p-IκB, and p-Akt.…”