Image1_Inhibitory Mechanism of Combined Hydroxychavicol With Epigallocatechin-3-Gallate Against Glioma Cancer Cell Lines: A Transcriptomic Analysis.pdf
Emerging reports have shown therapeutic potential of hydroxychavicol (HC) and epigallocatechin-3-gallate (EGCG) against cancer cells, however high concentrations are required to achieve the anticancer activity. We reported the synergy of low combination doses of EGCG+HC in glioma cell lines 1321N1, SW1783, and LN18 by assessing the effects of EGCG+HC through functional assays. Using high throughput RNA sequencing, the molecular mechanisms of EGCG+HC against glioma cell lines were revealed. EGCG/HC alone inhibited the proliferation of glioma cell lines, with IC50 values ranging from 82 to 302 µg/ml and 75 to 119 µg/ml, respectively. Sub-effective concentrations of combined EGCG+HC enhanced the suppression of glioma cell growth, with SW1783 showing strong synergism with a combination index (CI) of 0.55 and LN18 showing a CI of 0.51. A moderate synergistic interaction of EGCG+HC was detected in 1321N1 cells, with a CI value of 0.88. Exposure of 1321N1, SW1783, and LN18 cells to EGCG+HC for 24 h induces cell death, with caspase-3 activation rates of 52%, 57%, and 9.4%, respectively. However, the dose for SW1783 is cytotoxic to normal cells, thus this dose was excluded from other tests. EGCG+HC induced cell cycle arrest at S phase and reduced 1321N1 and LN18 cell migration and invasion. Combined EGCG+HC amplified its anticancer effect by downregulating the axon guidance process and metabolic pathways, while simultaneously interfering with endoplasmic reticulum unfolded protein response pathway. Furthermore, EGCG+HC exerted its apoptotic effect through the alteration of mitochondrial genes such as MT-CO3 and MT-RNR2 in 1321N1 and LN18 cells respectively. EGCG+HC dynamically altered DYNLL1 alternative splicing expression in 1321N1 and DLD splicing expression in LN18 cell lines. Our work indicated the pleiotropic effects of EGCG+HC treatment, as well as particular target genes that might be investigated for future glioma cancer therapeutic development.
History
References
- https://doi.org//10.1186/1472-6882-14-213
- https://doi.org//10.1007/s13105-019-00699-z
- https://doi.org//10.3390/molecules25143146
- https://doi.org//10.1007/s10555-018-9772-7
- https://doi.org//10.1016/j.yexmp.2020.104567
- https://doi.org//10.1016/j.fct.2015.08.017
- https://doi.org//10.1002/jcp.29451
- https://doi.org//10.7150/thno.37556
- https://doi.org//10.1158/0008-5472.CAN-09-1947
- https://doi.org//10.1016/0065-2571%2884%2990007-4
- https://doi.org//10.1371/journal.pone.0073672
- https://doi.org//10.1002/ptr.5643
- https://doi.org//10.1038/nrc3918
- https://doi.org//10.1016/j.taap.2014.07.012
- https://doi.org//10.1016/j.tcb.2020.03.002
- https://doi.org//10.1186/s12885-020-07694-4
- https://doi.org//10.1038/s42003-021-01667-4
- https://doi.org//10.1016/j.drudis.2018.01.021
- https://doi.org//10.1007/s00018-020-03536-5
- https://doi.org//10.2174/1574885516666210510185538
- https://doi.org//10.18632/oncotarget.3421
- https://doi.org//10.3389/fgene.2021.615834
- https://doi.org//10.1080/21655979.2019.1632669
- https://doi.org//10.3389/fphar.2020.568459
- https://doi.org//10.1038/nprot.2007.30
- https://doi.org//10.1186/s12885-019-6511-6
- https://doi.org//10.3390/cancers11050631
- https://doi.org//10.1142/S0192415X13500444
- https://doi.org//10.3390/cancers11060758
- https://doi.org//10.1016/j.ejmech.2019.111579
- https://doi.org//10.2147/OTT.S209441
- https://doi.org//10.1093/ntr/nty115
- https://doi.org//10.21873/anticanres.13793
- https://doi.org//10.1016/j.jnci.2017.04.001
- https://doi.org//10.1016/j.wneu.2021.04.096
- https://doi.org//10.1007/s00249-016-1141-2
- https://doi.org//10.3390/molecules190914528
- https://doi.org//10.3389/fphar.2020.00211
- https://doi.org//10.1093/biostatistics/kxm030
- https://doi.org//10.1016/j.taap.2013.05.004
- https://doi.org//10.1271/bbb.120882
- https://doi.org//10.7314/apjcp.2012.13.9.4815
- https://doi.org//10.3892/ijo.2014.2251
- https://doi.org//10.3389/fphys.2017.00231
- https://doi.org//10.21873/anticanres.13922
- https://doi.org//10.1111/j.1365-2710.2010.01237.x
- https://doi.org//10.1111/j.1749-6632.2011.06097.x
- https://doi.org//10.1038/nprot.2012.016
- https://doi.org//10.3892/or.2013.2734
- https://doi.org//10.1038/srep19225
- https://doi.org//10.1038/s41392-020-00359-5
- https://doi.org//10.1016/j.jarmap.2021.100320
- https://doi.org//10.1016/j.biopha.2014.12.016
- https://doi.org//10.1158/1078-0432.CCR-04-1087
- https://doi.org//10.7150/thno.38147
CC BY 4.0