Geniposide inhibits non-small cell lung cancer cell migration and angiogenesis by regulating PPARγ/VEGF-A pathway
Main Article Content
Keywords
geniposide, migration, angiogenesis, non-small cell lung cancer, PPARγ, VEGF-A
Abstract
Geniposide, an iridoid glycoside derived from traditional Chinese herb, Gardenia jasminoides Ellis, exerts antitumor effect against distinct cancers. The role of geniposide in the migration and angiogenesis of non-small cell lung cancer (NSCLC) cell was investigated in this study. Cancer cells were incubated with various concentrations of geniposide, and proliferative ability was detected by Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) staining. Wound healing and transwell were used to assess cell migration and invasion, respectively. Tube formation assay was performed to investigate angiogenesis. Geniposide reduced NSCLC cell proliferation, and suppressed NSCLC cell migration and invasion in a dosage-dependent manner. Angiogenesis of NSCLC was also inhibited by geniposide. Geniposide increased the protein expression of peroxisome proliferator-activated receptor gamma (PPARγ) and decreased vascular endothelial growth factor-A (VEGF-A) protein expression in NSCLC cells. Incubation with a PPARγ antagonist, GW9662, attenuated geniposide-induced up-regulation of PPARγ and down-regulation of VEGF-A. Over-expression of VEGF-A weakened geniposide-suppressed cell proliferation, migration, and angiogenesis of NSCLC. Geniposide exerted antitumor and anti-angiogenic actions on NSCLC through regulation of PPARγ/VEGF-A pathway.
References
Cheng, Z., Xu, H., Wang, X. and Liu, Z., 2017. Lactobacillus raises in vitro anticancer effect of geniposide in HSC-3 human oral squamous cell carcinoma cells. Experimental and Therapeutic Medicine 14: 4586–4594. 10.3892/etm.2017.5105
D’Amico, T.A., 2004. Angiogenesis in non-small cell lung cancer. Seminars in Thoracic and Cardiovascular Surgery 16: 13–18. 10.1053/j.semtcvs.2004.01.003
Elkhider, A., Wang, B., Ouyang, X., Al-Azab, M., Walana, W., Sun, X., Li, H., Tang, Y., Wei, J. and Li, X., 2020. Aquaporin 5 promotes tumor migration and angiogenesis in non-small cell lung cancer cell line H1299. Oncology Letters 19: 1665–1672. 10.3892/ol.2020.11251. Epub 2020 Jan 7
Garon, E.B., Hellmann, M.D., Rizvi, N.A., Carcereny, E., Leighl, N.B., Ahn, M.-J., Eder, J.P., Balmanoukian, A.S., Aggarwal, C., Horn, L., Patnaik, A., Gubens, M., Ramalingam, S.S., Felip, E., Goldman, J.W., Scalzo, C., Jensen, E., Kush, D.A. and Hui, R., 2019. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 37: 2518–2527. 10.1200/JCO.19.00934
Gridelli, C., Rossi, A., Carbone, D.P., Guarize, J., Karachaliou, N., Mok, T., Petrella, F., Spaggiari, L. and Rosell, R., 2015. Non-small-cell lung cancer. Nature Reviews Disease Primers 1: 15009. 10.1038/nrdp.2015.9
Guo, L.-x., Liu, J.-h. and Xia, Z.-n., 2009. Geniposide inhibits CoCl2-induced PC12 cells death via the mitochondrial pathway. Chinese Medical Journal 122(23): 2886-2892. PMid: 2009279
Habtemariam, S. and Lentini, G., 2018. Plant-derived anticancer agents: lessons from the pharmacology of geniposide and its aglycone, genipin. Biomedicines 6: 39. 10.3390/biomedicines6020039
Han, S.W. and Roman, J., 2010. Anticancer actions of PPARγ ligands: current state and future perspectives in human lung cancer. World Journal of Biological Chemistry 1: 31–40. 10.4331/wjbc.v1.i3.31
Hong, M., Lee, S., Clayton, J., Yake, W. and Li, J., 2020. Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3. Journal of Experimental & Clinical Cancer Research 39: 1–17. 10.1186/s13046-020-01654-3
Hu, L., Zhao, J., Liu, Y., Liu, X., Lu, Q., Zeng, Z., Zhu, L., Tong, X. and Xu, Q., 2020. Geniposide inhibits proliferation and induces apoptosis of diffuse large B-cell lymphoma cells by inactivating the HCP5/miR-27b-3p/MET axis. International Journal of Medical Sciences 17: 2735–2743. 10.7150/ijms.51329
Jin, Z., Zhao, H., Luo, Y., Li, J., Pi, J., He, W., Yan, J. and Yang, P., 2021. Geniposide achieved an anti-inflammatory effect through the NF-κB/HIF-1α signaling pathway mediated by VEGFA and HMOX1 genes.
Keedy, V.L. and Sandler, A.B., 2007. Inhibition of angiogenesis in the treatment of non-small cell lung cancer. Cancer Science 98: 1825–1830. 10.1111/j.1349-7006.2007.00620.x
Kim, Y.H., Nagai, H., Ozasa, H., Sakamori, Y. and Mishima, M., 2013. Therapeutic strategy for non-small-cell lung cancer patients with brain metastases (review). Biomedical Reports 1: 691–696. 10.3892/br.2013.151
Li, N., Li, L., Wu, H. and Zhou, H., 2019. Antioxidative property and molecular mechanisms underlying geniposide-mediated therapeutic effects in diabetes mellitus and cardiovascular disease. Oxidative Medicine and Cellular Longevity 2019: 7480512. 10.1155/2019/7480512
Lichota, A. and Gwozdzinski, K., 2018. Anticancer activity of natural compounds from plant and marine environment. International Journal of Molecular Sciences 19: 3533. 10.3390/ijms19113533
Liu, J., Guo, L., Yin, F., Zhang, Y., Liu, Z. and Wang, Y., 2013. Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells. PloS One 8: e78315. 10.1371/journal.pone.0078315
Liu, J.-H., Yin, F., Guo, L.-X., Deng, X.-H. and Hu, Y.-H., 2009. Neuroprotection of geniposide against hydrogen peroxide-induced PC12 cells injury: involvement of PI3 kinase signal pathway. Acta Pharmacologica Sinica 30: 159–165. 10.1038/aps.2008.25
Liu, J., Zhao, N., Shi, G. and Wang, H., 2020. Geniposide ameliorated sepsis-induced acute kidney injury by activating PPARγ. Aging 12: 22744–22758. 10.18632/aging.103902
Liu, Z.-l., Zhu, W.-r., Zhou, W.-c., Ying, H.-f., Zheng, L., Guo, Y.-b., Chen, J.-x. and Shen, X.-h., 2014. Traditional Chinese medicinal herbs combined with epidermal growth factor receptor tyrosine kinase inhibitor for advanced non-small cell lung cancer: a systematic review and meta-analysis. Journal of Integrative Medicine 12: 346–358. 10.1016/S2095-4964(14)60034-0
Loong, H.H., Kwan, S.-c.S., Mok, T.S.-k. and Lau, Y.-m., 2018. Therapeutic strategies in EGFR mutant non-small cell lung cancer. Current Treatment Options in Oncology 19: 58. 10.1007/s11864-018-0570-9
Ma, J. and Ding, Y., 2018. Geniposide suppresses growth, migration and invasion of MKN45 cells by down-regulation of lncRNA HULC. Experimental and Molecular Pathology 105: 252–259. 10.1016/j.yexmp.2018.08.011
Malapelle, U. and Rossi, A., 2019. Emerging angiogenesis inhibitors for non-small cell lung cancer. Expert Opinion on Emerging Drugs 24: 71–81. 10.1080/14728214.2019.1619696
Onuma, H., Inukai, K., Kitahara, A., Moriya, R., Nishida, S., Tanaka, T., Katsuta, H., Takahashi, K., Sumitani, Y. and Hosaka, T., 2014. The glucagon-like peptide 1 receptor agonist enhances intrinsic peroxisome proliferator-activated receptor γ activity in endothelial cells. Biochemical and Biophysical Research Communications 451: 339–344. 10.1016/j.bbrc.2014.07.136
Thawani, R., Fakhoury, K. and Becker, K.D., 2020. Cause of mortality in patients with lung cancer and brain metastasis. Journal of Clinical Oncology 38: e21743. 10.1200/JCO.2020.38.15_suppl.e21743
Tian, J., Hu, L., Li, X., Geng, J., Dai, M. and Bai, X., 2016. MicroRNA-130b promotes lung cancer progression via PPARγ/VEGF-A/BCL-2-mediated suppression of apoptosis. Journal of Experimental & Clinical Cancer Research 35: 105–105. 10.1186/s13046-016-0382-3
Wang, Y., Wu, H., Deng, R., Dai, X.j., Bu, Y.h., Sun, M.h., Zhang, H., Wang, M.d. and Wang, R.h., 2021. Geniposide downregulates the VEGF/SphK1/S1P pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro. Phytotherapy Research 35(8): 4347–4362. 10.1002/ptr.7130
Yang, X., Lei, P., Huang, Y., Zhang, Z. and Zhang, Y., 2016. MicroRNA-133b inhibits the migration and invasion of non small cell lung cancer cells via targeting FSCN1. Oncology Letters 12: 3619–3625. 10.3892/ol.2016.5044
Yang, X., Yao, J., Luo, Y., Han, Y., Wang, Z. and Du, L., 2013. P38 MAP kinase mediates apoptosis after genipin treatment in non-small-cell lung cancer H1299 cells via a mitochondrial apoptotic cascade. Journal of Pharmacological Sciences 121: 272–281. 10.1254/jphs.12234fp
Yoshizaki, T., Motomura, W., Tanno, S., Kumei, S., Yoshizaki, Y., Tanno, S. and Okumura, T., 2010. Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells. Journal of Experimental & Clinical Cancer Research 29: 22. 10.1186/1756-9966-29-22
Yu, X., Wang, Y., Tao, S. and Sun, S., 2020. Geniposide plays anti-tumor effects by down-regulation of microRNA-224 in HepG2 and Huh7 cell lines. Experimental and Molecular Pathology 112: 104349. 10.1016/j.yexmp.2019.104349
Zhang, X.-W., Liu, W., Jiang, H.-L. and Mao, B., 2018. Chinese herbal medicine for advanced non-small-cell lung cancer: a systematic review and meta-analysis. American Journal of Chinese Medicine 46: 923–952. 10.1142/S0192415X18500490
Zhang, C., Wang, N., Tan, H.-Y., Guo, W., Chen, F., Zhong, Z., Man, K., Tsao, S.W., Lao, L. and Feng, Y., 2020. Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIf 1Ñ independent VEGF expression and angiogenesis in hepatocellular carcinoma. British Journal of Pharmacology 177: 3240–3257. 10.1111/bph.15046
Zhang, B., Wu, T., Wang, Z., Zhang, Y., Wang, J., Yang, B., Zhao, Y., Rao, Z. and Gao, J., 2015. p38MAPK activation mediates tumor necrosis Factor-α-induced apoptosis in glioma cells. Molecular Medicine Reports 11: 3101–3107. 10.3892/mmr.2014.3002
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Ming Jiang, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China; Gaoyou People’s Hospital, Yangzhou, Jiangsu Province, China.
Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
Department of Thoracic Surgery, Gaoyou People’s Hospital, Yangzhou, Jiangsu Province, China
Shiying Zheng, The First Affiliated Hospital of Soochow University, Suzhou Jiangsu Province, China
Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou Jiangsu Province, China