Brusatol inhibits the growth of prostate cancer cells and reduces HIF-1α/VEGF expression and glycolysis under hypoxia
Main Article Content
Keywords
Brusatol, hypoxia, HIF-1α, prostate cancer, VEGF, glycolysis
Abstract
Prostate cancer (PCa) has a high rate of morbidity and mortality, which urges us to find a unique and effective drug for treatment. Brusatol, a triterpenoid-degraded derivative, possesses antitumor activities. However, the significance of Brusatol in prostate cancer has not yet been completely elucidated. Therefore, this study aimed to explore how Brusatol affected prostate cancer cells. DU145 and PC-3 cell lines were chosen as experimental models. After Brusatol was added to relevant cells in culture, CCK-8 and colony formation experiments were used to assess cell viability; apoptosis rates were calculated using flow cytometry; and transwell assays were utilized to assess cell migration and invasion ability. Vimentin, N-cadherin, E-cadherin, zonula occludens-1 (ZO-1), hypoxia- inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase (LDHA) protein expression were evaluated by western blotting, and glucose consumption in cells was assessed using related equipment. In DU145 and PC-3 cells, Brusatol drastically reduced cell proliferation, promoted apoptosis, hindered migration and invasion. Considerably decreased HIF-1α and VEGF protein levels under hypoxia were detected. Furthermore, the expression of GLUT1, HK2, and LDHA was diminished, resulting in decreased glucose consumption in a Brusatol concentration-dependent manner. These findings demonstrate that Brusatol serves as a potent antitumor drug that suppresses DU145 and PC-3 cancer cell growth, metastasis, and glycolysis. This discovery could provide a possible clinical treatment strategy for prostate cancer.
References
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Fang, C., Dai, L., Wang, C., Fan, C., Yu, Y., Yang, L., Deng, H. and Zhou, Z., 2021. Secretogranin II impairs tumor growth and angiogenesis by promoting degradation of hypoxia-inducible factor-1α in colorectal cancer. Molecular Oncology 15: 3513–3526. 10.1002/1878-0261.13044
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Moon, E.J., Mello, S.S., Li, C.G., Chi, J.-T., Thakkar, K., Kirkland, J.G., Lagory, E.L., Lee, I.J., Diep, A.N., Miao, Y., Rafat, M., Vilalta, M., Castellini, L., Krieg, A.J., Graves, E.E., Attardi, L.D. and Giaccia, A.J., 2021. The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nature Communications 12: 4308. 10.1038/s41467-021-24631-6
Mu, G., Zhu, Y., Dong, Z., Shi, L., Deng, Y. and Li, H., 2021. Calmodulin 2 facilitates angiogenesis and metastasis of gastric cancer STAT3/HIF-1A/VEGF-a mediated macrophage polarization. Frontiers in Oncology 11: 727306. 10.3389/fonc.2021.727306
Nishimura, M., Fuchino, H., Takayanagi, K., Kawakami, H., Nakayama, H., Kawahara, N. and Shimada, Y., 2021. Toxicity of Jegosaponins A and B from Siebold et al. zuccarini in prostate cancer cells and zebrafish embryos resulting from increased membrane permeability. International Journal of Molecular Sciences 22: 6354. 10.3390/ijms22126354
Oh, E.-T., Kim, C.W., Kim, H.G., Lee, J.-S. and Park, H.J., 2017. Brusatol-mediated inhibition of c-Myc increases HIF-1α degradation and causes cell death in colorectal cancer under hypoxia. Theranostics 7: 3415–3431. 10.7150/thno.20861
Palazon, A., Goldrath, A. W., Nizet, V. and Johnson, R. S., 2014. HIF transcription factors, inflammation, and immunity. Immunity 41: 518-528. 10.1016/j.immuni.2014.09.008
Roncati, L., Vadala, M., Corazzari, V. and Palmieri, B., 2021. Immunohistochemical expression of cannabinoid receptors in women’s cancers: what’s new? European Journal of Gynaeco-logical Oncology 42: 193–195. 10.31083/j.ejgo.2021.02.5463
Semenza, G.L., 2003. Targeting HIF-1 for cancer therapy. Nature Reviews Cancer 3: 721–732. 10.1038/nrc1187
Siegel, R.L., Miller, K.D. and Jemal, A., 2020. Cancer statistics, 2020. CA: A Cancer Journal for Clinicians 70: 7–30. 10.3322/caac.21590
Vander Heiden, M.G., Cantley, L.C. and Thompson, C.B., 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324: 1029–1033. 10.1126/science.1160809
Vaupel, P. and Mayer, A., 2007. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Reviews 26: 225–239. 10.1007/s10555-007-9055-1
Wang, K., Ruan, H., Xu, T., Liu, L., Liu, D., Yang, H., Zhang, X. and Chen, K., 2018. Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer. OncoTargets and Therapy 11: 3167–3178. 10.2147/OTT.S159777
Wang, M., Shi, G., Bian, C., Nisar, M.F., Guo, Y., Wu, Y., Li, W., Huang, X., Jiang, X., Bartsch, J.W., Ji, P. and Zhong, J.L., 2018. UVA irradiation enhances brusatol-mediated inhibition of melanoma growth by downregulation of the Nrf2-mediated antioxidant response. Oxidative Medicine and Cellular Longevity 2018: 9742154. 10.1155/2018/9742154
Wang, T., Dou, Y., Lin, G., Li, Q., Nie, J., Chen, B., Xie, J., Su, Z., Zeng, H., Chen, J. and Xie, Y., 2021. The anti-hepatocellular carcinoma effect of Brucea javanica oil in ascitic tumor-bearing mice: the detection of brusatol and its role. Biomedicine & Pharmacotherapy 134: 111122. 10.1016/j.biopha.2020.111122
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