Genistein Promotes Apoptosis of Lung Cancer Cells Through the IMPDH2/AKT1 Pathway

Overview

Journal Am J Transl Res

Specialty General Medicine

Date 2022 Nov 18

PMID 36398246

Authors

Hao Xu

Hongda Ma

Lifen Zha

Qian Li

Huiming Pan

Ladi Zhang

Affiliations

Soon will be listed here.

Abstract

Objective: Lung cancer (LC) is a clinically challenging cancer. Genistein is a natural isoflavone product with anti-tumor effects. This study aims to investigate the effect of genistein on A549 cell apoptosis, to provide more experimental evidence for clinical treatment.

Methods: Real-time quantitative polymerase chain reaction, western blotting, molecular docking, and target prediction methods were performed to detect the effect of genistein on LC cells. Cell viability of A549 treated by genistein was measured by a CCK-8 assay. The A549 cell apoptosis after genistein treatment was detected by flow cytometry.

Results: Genistein promoted the apoptosis of LC cells in a time- and concentration-dependent manner. In addition, the low expression of inosine monophosphate dehydrogenase-2 (IMPDH2) inhibited the effect of genistein on LC cells. By predicting IMPDH2 LC-related apoptosis genes and finding the closely related gene protein kinase B (AKT1), it was found that the highly expressed AKT1 inhibited the effect of genistein on LC cell apoptosis and viability.

Conclusion: Genistein may be a promising treatment for LC.

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References

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

Collart F, Chubb C, Mirkin B, Huberman E . Increased inosine-5'-phosphate dehydrogenase gene expression in solid tumor tissues and tumor cell lines. Cancer Res. 1992; 52(20):5826-8. DOI: 10.2172/10148922. View

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

Jackson R, Weber G, MORRIS H . IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature. 1975; 256(5515):331-3. DOI: 10.1038/256331a0. View

Colby T, Vanderveen K, Strickler M, Markham G, Goldstein B . Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc Natl Acad Sci U S A. 1999; 96(7):3531-6. PMC: 22327. DOI: 10.1073/pnas.96.7.3531. View

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. DOI: 10.3322/caac.20107. View

Ramos S . Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem. 2007; 18(7):427-42. DOI: 10.1016/j.jnutbio.2006.11.004. View

Cornwell T, Cohick W, Raskin I . Dietary phytoestrogens and health. Phytochemistry. 2004; 65(8):995-1016. DOI: 10.1016/j.phytochem.2004.03.005. View

Ni J, Cozzi P, Hao J, Beretov J, Chang L, Duan W . Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int J Biochem Cell Biol. 2013; 45(12):2736-48. DOI: 10.1016/j.biocel.2013.09.008. View

10.

Penuelas S, Noe V, Ciudad C . Modulation of IMPDH2, survivin, topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells. FEBS J. 2005; 272(3):696-710. DOI: 10.1111/j.1742-4658.2004.04504.x. View

11.

Hers I, Vincent E, Tavare J . Akt signalling in health and disease. Cell Signal. 2011; 23(10):1515-27. DOI: 10.1016/j.cellsig.2011.05.004. View

12.

Konno Y, Natsumeda Y, Nagai M, Yamaji Y, Ohno S, Suzuki K . Expression of human IMP dehydrogenase types I and II in Escherichia coli and distribution in human normal lymphocytes and leukemic cell lines. J Biol Chem. 1991; 266(1):506-9. View

13.

Manning B, Cantley L . AKT/PKB signaling: navigating downstream. Cell. 2007; 129(7):1261-74. PMC: 2756685. DOI: 10.1016/j.cell.2007.06.009. View

14.

Pua K, Stiles D, Sowa M, Verdine G . IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex. Cell Rep. 2017; 18(2):432-442. DOI: 10.1016/j.celrep.2016.12.030. View

15.

Massague J . G1 cell-cycle control and cancer. Nature. 2004; 432(7015):298-306. DOI: 10.1038/nature03094. View

16.

Shu Q, Nair V . Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery. Med Res Rev. 2007; 28(2):219-32. DOI: 10.1002/med.20104. View

17.

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

18.

Aggarwal B, Shishodia S . Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci. 2005; 1030:434-41. DOI: 10.1196/annals.1329.054. View

19.

Wu T, Peng Y, Pelleymounter L, Moon I, Eckloff B, Wieben E . Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics. Br J Pharmacol. 2010; 161(7):1584-98. PMC: 3010569. DOI: 10.1111/j.1476-5381.2010.00987.x. View

20.

McDonald P, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V . Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res. 2008; 68(6):1618-24. DOI: 10.1158/0008-5472.CAN-07-5869. View