Genistein Inhibits Lung Cancer Cell Stem-like Characteristics by Modulating MnSOD and FoxM1 Expression

Overview

Journal Oncol Lett

Specialty Oncology

Date 2020 Aug 13

PMID 32782570

Citations 11

Authors

Zhimin Fu

Xiaocheng Cao

Lihua Liu

Xiaozheng Cao

Yinghong Cui

Xiang Li

Meifang Quan

Kaiqun Ren

A Chen

Chang Xu

Yebei Qiu

Xiangding Chen

Zheng Wang

Jianguo Cao

Affiliations

Soon will be listed here.

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.

Citing Articles

Cellular and Molecular Mechanisms Modulated by Genistein in Cancer.

Naponelli V, Piscazzi A, Mangieri D Int J Mol Sci. 2025; 26(3).

PMID: 39940882 PMC: 11818640. DOI: 10.3390/ijms26031114.

Bioinformatics-based drug repositioning and prediction of the main active ingredients and potential mechanisms of action for the efficacy of Dan-Lou tablet.

Zhang J, Lin Z, Zhang Y, Gu H, Li W Sci Rep. 2024; 14(1):23297.

PMID: 39375410 PMC: 11458610. DOI: 10.1038/s41598-024-74243-5.

Identifying the Multitarget Pharmacological Mechanism of Action of Genistein on Lung Cancer by Integrating Network Pharmacology and Molecular Dynamic Simulation.

Das R, Woo J Molecules. 2024; 29(9).

PMID: 38731403 PMC: 11085736. DOI: 10.3390/molecules29091913.

The Role of Genistein and its Derivatives in Ovarian Cancer: New Perspectives for Molecular Mechanisms and Clinical Applications.

Chaichian S, Chaichian S, Nikfar B, Bidgoli S, Moazzami B Curr Med Chem. 2023; 32(5):907-922.

PMID: 37921172 DOI: 10.2174/0109298673251713231019091910.

Application of Polyphenols and Flavonoids in Oncological Therapy.

Roszkowski S Molecules. 2023; 28(10).

PMID: 37241819 PMC: 10220832. DOI: 10.3390/molecules28104080.

References

Fan P, Fan S, Wang H, Mao J, Shi Y, Ibrahim M . Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway. Stem Cell Res Ther. 2013; 4(6):146. PMC: 4054948. DOI: 10.1186/scrt357. View

Xiang H, Liu F, Quan M, Cao J, Lv Y . 7-difluoromethoxyl-5,4'-di-n-octylgenistein inhibits growth of gastric cancer cells through downregulating forkhead box M1. World J Gastroenterol. 2012; 18(33):4618-26. PMC: 3435790. DOI: 10.3748/wjg.v18.i33.4618. View

Prietsch R, Monte L, da Silva F, Beira F, Del Pino F, Campos V . Genistein induces apoptosis and autophagy in human breast MCF-7 cells by modulating the expression of proapoptotic factors and oxidative stress enzymes. Mol Cell Biochem. 2014; 390(1-2):235-42. DOI: 10.1007/s11010-014-1974-x. View

Ning Y, Li Q, Xiang H, Liu F, Cao J . Apoptosis induced by 7-difluoromethoxyl-5,4'-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells. Oncol Rep. 2012; 27(6):1857-64. DOI: 10.3892/or.2012.1739. View

Wang Z, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar F . Forkhead box M1 transcription factor: a novel target for cancer therapy. Cancer Treat Rev. 2009; 36(2):151-6. PMC: 2838950. DOI: 10.1016/j.ctrv.2009.11.006. View

Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A . Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2007; 15(3):504-14. DOI: 10.1038/sj.cdd.4402283. View

Engel N, Adamus A, Schauer N, Kuhn J, Nebe B, Seitz G . Synergistic Action of Genistein and Calcitriol in Immature Osteosarcoma MG-63 Cells by SGPL1 Up-Regulation. PLoS One. 2017; 12(1):e0169742. PMC: 5268493. DOI: 10.1371/journal.pone.0169742. View

Su Y, Lin W, Chang Y, Wei K, Liang C, Chen S . Polarized cell migration induces cancer type-specific CD133/integrin/Src/Akt/GSK3β/β-catenin signaling required for maintenance of cancer stem cell properties. Oncotarget. 2015; 6(35):38029-45. PMC: 4741982. DOI: 10.18632/oncotarget.5703. View

Kopanja D, Pandey A, Kiefer M, Wang Z, Chandan N, Carr J . Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol. 2015; 63(2):429-36. PMC: 4508215. DOI: 10.1016/j.jhep.2015.03.023. View

10.

Sanders H, Albitar M . Somatic mutations of signaling genes in non-small-cell lung cancer. Cancer Genet Cytogenet. 2010; 203(1):7-15. DOI: 10.1016/j.cancergencyto.2010.07.134. View

11.

Su J, Wu S, Wu H, Li L, Guo T . CD44 is functionally crucial for driving lung cancer stem cells metastasis through Wnt/β-catenin-FoxM1-Twist signaling. Mol Carcinog. 2015; 55(12):1962-1973. DOI: 10.1002/mc.22443. View

12.

Cui S, Wang J, Wu Q, Qian J, Yang C, Bo P . Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways. Oncotarget. 2017; 8(13):21674-21691. PMC: 5400615. DOI: 10.18632/oncotarget.15535. View

13.

Xing Z, Yu G, Qin L, Jiang F, Zhao W . Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells. Genet Mol Res. 2015; 14(4):13880-8. DOI: 10.4238/2015.October.29.8. View

14.

Jiang F, Qiu Q, Khanna A, Todd N, Deepak J, Xing L . Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res. 2009; 7(3):330-8. PMC: 4255559. DOI: 10.1158/1541-7786.MCR-08-0393. View

15.

Antosiak A, Milowska K, Maczynska K, Rozalska S, Gabryelak T . Cytotoxic activity of genistein-8-C-glucoside form L. and genistein against human SK-OV-3 ovarian carcinoma cell line. Med Chem Res. 2017; 26(1):64-73. PMC: 5219005. DOI: 10.1007/s00044-016-1725-5. View

16.

Huang W, Wan C, Luo Q, Huang Z, Luo Q . Genistein-inhibited cancer stem cell-like properties and reduced chemoresistance of gastric cancer. Int J Mol Sci. 2014; 15(3):3432-43. PMC: 3975346. DOI: 10.3390/ijms15033432. View

17.

Kong X, Li L, Li Z, Le X, Huang C, Jia Z . Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. Cancer Res. 2013; 73(13):3987-96. PMC: 3702645. DOI: 10.1158/0008-5472.CAN-12-3859. View

18.

Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A . Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem. 2011; 112(9):2296-306. PMC: 3155646. DOI: 10.1002/jcb.23150. View

19.

Liu S, Chen Q, Guo L, Cao X, Sun X, Chen W . Incidence and mortality of lung cancer in China, 20082012. Chin J Cancer Res. 2019; 30(6):580-587. PMC: 6328502. DOI: 10.21147/j.issn.1000-9604.2018.06.02. View

20.

Chen P, Cheng Y, Wu T, Chen C, Lee H . MnSOD overexpression confers cisplatin resistance in lung adenocarcinoma via the NF-κB/Snail/Bcl-2 pathway. Free Radic Biol Med. 2014; 79:127-37. DOI: 10.1016/j.freeradbiomed.2014.12.001. View