Ampelopsin induces MDA-MB-231 cell cycle arrest through cyclin B1-mediated PI3K/AKT/mTOR pathway in vitro and in vivo

Meng, Minjun; Yang, Qiaolu; Ouyang, Zhong; Yang, Qingmo; Wu, Xinyi; Huang, Yufan; Su, Yonghui; Chen, Shuanglong; Chen, Wenlin

doi:10.2478/acph-2023-0005

Abstract

Breast cancer is one of the most common malignant tumors in women and it is the most frequently diagnosed cancer in the world. Ampelopsin (AMP) is a purified component from the root of Ampelopsis grossedentata. It is reported that AMP could significantly inhibit the proliferation of breast cancer cells. However, the antitumor mechanism against breast cancer has not yet been fully elucidated. The purpose of this work was to study the role of AMP against breast cancer MDA-MB-231 cells and to further investigate the underlying mechanism. PI3K/AKT/mTOR plays a very important role in tumor cell growth and proliferation and we hypothesize that AMP may inhibit this pathway. In the present work, the results showed that AMP could significantly inhibit the growth of breast cancer MDA-MB-231 cells in vitro and in vivo. In addition, treatment with AMP decreased the levels of PI3K, AKT and mTOR, as well as cyclin B1 expression, followed by p53/p21 pathway activation to arrest the cell cycle at G2/M. Moreover, it demonstrated a positive association between cyclin B1 and PI3K/AKT/mTOR levels. Importantly, this pathway was found to be regulated by cyclin B1 in MDA-MB-231 cells treated with AMP. Also, it was observed that cyclin B1 overexpression attenuated cell apoptosis and weakened the inhibitory effects of AMP on cell proliferation. Together, AMP could inhibit breast cancer MDA-MB-231 cell proliferation in vitro and in vivo, due to cell cycle arrest at G2/M by inactivating PI3K/AKT/mTOR pathway regulated by cyclin B1.

References

1. M. S. Kim, C. W. Lee, J. H. Kim, J. C. Lee and W. G. An, Extract of rhus verniciflua stokes induces p53-mediated apoptosis in MCF-7 breast cancer cells, Evid. Based Complement. Alternat. Med. 2019 (2019) Article ID 9407340 (10 pages); https://doi.org/10.1155/2019/9407340638342730881477
Search in Google Scholar Back to article
2. H. Sung, J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal and F. Bray, Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 71(3) (2021) 209–249; https://doi.org/10.3322/caac.2166033538338
Search in Google Scholar Back to article
3. R. Venkatadri, T. Muni, A. K. Iyer, J. S. Yakisich and N. Azad, Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death, Cell Death Dis. 7 (2016) e2104; (12 pages) https://doi.org/10.1038/cddis.2016.6539919426890143
Search in Google Scholar Back to article
4. C. A. Dehelean, I. Marcovici, C. Soica, M. Mioc, D. Coricovac, S. Iurciuc, O. M. Cretu and I. Pinzaru, Plant-derived anticancer compounds as new perspectives in drug discovery and alternative therapy, Molecules 26 (2021) Article ID 1109 (29 pages); https://doi.org/10.3390/molecules26041109792218033669817
Search in Google Scholar Back to article
5. V. Singh, K. Kumar, D. Purohit, R. Verma, P. Pandey, S. Bhatia, V. Malik, V. Mittal, M. H. Rahman, G. M. Albadrani, M. W. Arafah, F. M. El-Demerdash, M. F. Akhtar, A. Saleem, M. Kamel, A. Najda, M. M. Abdel-Daim and D. Kaushik, Exploration of therapeutic applicability and different signaling mechanism of various phytopharmacological agents for treatment of breast cancer, Biomed. Pharmacother. 139 (2021) Article ID 111584 (19 pages); https://doi.org/10.1016/j.biopha.2021.11158434243623
Search in Google Scholar Back to article
6. V. M. Dan, R. S. Raveendran and S. Baby, Resistance to intervention: paclitaxel in breast cancer, Mini Rev. Med. Chem. 21 (2021) 1237–1268; https://doi.org/10.2174/138955752099920121423442133319669
Search in Google Scholar Back to article
7. S. Qi, Y. Xin, Y. Guo, Y. Diao, X. Kou, L. Luo and Z. Yin, Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-κB signaling pathways, Int. Immunopharmacol. 12(1) (2012) 278–287; https://doi.org/10.1016/j.intimp.2011.12.00122193240
Search in Google Scholar Back to article
8. V. N. Truong, Y. T. Nguyen and S. K. Cho, Ampelopsin suppresses stem cell properties accompanied by attenuation of oxidative phosphorylation in chemo- and radio-resistant MDA-MB-231 breast cancer cells, Pharmaceuticals (Basel) 14 (2021) Article ID 794 (17 pages); https://doi.org/10.3390/ph14080794840066534451892
Search in Google Scholar Back to article
9. X. Kou, J. Fan and N. Chen, Potential molecular targets of ampelopsin in prevention and treatment of cancers, Anticancer Agents Med. Chem. 17(12) (2017) 1610–1616; https://doi.org/10.2174/187152140966617041213052928403777
Search in Google Scholar Back to article
10. H. Chang, X. Peng, Q. Bai, Y. Zhou, X. Yu, Q. Zhang, J. Zhu and M. Mi, Ampelopsin suppresses breast carcinogenesis by inhibiting the mTOR signalling pathway, Carcinogenesis 35(8) (2014) 1847–1854; https://doi.org/10.1093/carcin/bgu11824861637
Search in Google Scholar Back to article
11. T. Otto and P. Sicinski, Cell cycle proteins as promising targets in cancer therapy, Nat. Rev. Cancer 17 (2017) 93–115; https://doi.org/10.1038/nrc.2016.138534593328127048
Search in Google Scholar Back to article
12. J. C. Bendell, J. Rodon, H. A. Burris, M. de Jonge, J. Verweij, D. Birle, D. Demanse, S. S. De Buck, Q. C. Ru, M. Peters, M. Goldbrunner and J. Baselga, Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors, J. Clin. Oncol. 30(3) (2012) 282–290; https://doi.org/10.1200/JCO.2011.36.136022162589
Search in Google Scholar Back to article
13. D. Gong and J. E. Jr. Ferrell, The roles of cyclin A2, B1 and B2 in early and late mitotic events, Mol. Biol. Cell 21(18) (2010) 3149–3161; https://doi.org/10.1091/mbc.E10-05-0393293838120660152
Search in Google Scholar Back to article
14. F. Fei, J. Qu, K. Liu, C. Li, X. Wang, Y. Li and S. Zhang, The subcellular location of cyclin B1 and CDC25 associated with the formation of polyploid giant cancer cells and their clinicopathological significance, Lab. Invest. 99 (2019) 483–498; https://doi.org/10.1038/s41374-018-0157-x30487595
Search in Google Scholar Back to article
15. T. K. Fung, H. T. Ma and R. Y. Poon, Specialized roles of the two mitotic cyclins in somatic cells: cyclin A as an activator of M phase-promoting factor, Mol. Biol. Cell 18(5) (2007) 1861–1873; https://doi.org/10.1091/mbc.e06-12-1092185502317344473
Search in Google Scholar Back to article
16. Y. Lu, G. Yang, Y. Xiao, T. Zhang, F. Su, R. Chang, X. Ling and Y. Bai, Upregulated cyclins may be novel genes for triple-negative breast cancer based on bioinformatic analysis, Breast Cancer 27 (2020) 903–911; https://doi.org/10.1007/s12282-020-01086-z32338339
Search in Google Scholar Back to article
17. B. Li, H. B. Zhu, G. D. Song, J. H. Cheng, C. Z. Li, Y. Z. Zhang and P. Zhao, Regulating the CCNB1 gene can affect cell proliferation and apoptosis in pituitary adenomas and activate epithelial-tomesenchymal transition, Oncol. Lett. 18(5) (2019) 4651–4658; https://doi.org/10.3892/ol.2019.10847678151831611974
Search in Google Scholar Back to article
18. J. A. Engelman, J. Luo and L. C. Cantley, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism, Nat. Rev. Genet. 7 (2006) 606–619; https://doi.org/10.1038/nrg187916847462
Search in Google Scholar Back to article
19. A. Ghoneum and N. Said, PI3K-AKT-mTOR and NFκB pathways in ovarian cancer: implications for targeted therapeutics, Cancers 11 (2019) Article ID 949 (26 pages); https://doi.org/10.3390/cancers11070949667909531284467
Search in Google Scholar Back to article
20. B. Zhang, Z. Zhao, X. Meng, H. Chen, G. Fu and K. Xie, Hydrogen ameliorates oxidative stress via PI3K-Akt signaling pathway in UVB-induced HaCaT cells, Int. J. Mol. Med. 41(6) (2018) 3653–3661; https://doi.org/10.3892/ijmm.2018.355029532858
Search in Google Scholar Back to article
21. E. Paplomata and R. O’Regan, The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers, Ther. Adv. Med. Oncol. 6(4) (2014) 154–166; https://doi.org/10.1177/1758834014530023410771225057302
Search in Google Scholar Back to article
22. D. Miricescu, A. Totan, I. I. Stanescu-Spinu, S. C. Badoiu, C. Stefani and M. Greabu, PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects, Int. J. Mol. Sci. 22(1) (2020) Article ID 173 (24 pages); https://doi.org/10.3390/ijms22010173779601733375317
Search in Google Scholar Back to article
23. S. Aggarwal, S. John, L. Sapra, S. C. Sharma and S. N. Das, Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells, Cancer Chemother. Pharmacol. 83 (2019) 451–461; https://doi.org/10.1007/s00280-018-3746-x30519710
Search in Google Scholar Back to article
24. A. Narayanankutty, Phytochemicals as PI3K/Akt/mTOR inhibitors and their role in breast cancer treatment, Recent Pat. Anticancer Drug Discov. 15(3) (2020) 188–199; https://doi.org/10.2174/157489281566620091016464132914720
Search in Google Scholar Back to article
25. J. H. Lin, P. C. Ting, W. S. Lee, H. W. Chiu, C. A. Chien, C. H. Liu, L. Y. Sun and K. T. Yang, Palmitic acid methyl ester induces G2/M arrest in human bone marrow-derived mesenchymal stem cells via the p53/p21 pathway, Stem Cells Int. 2019 (2019) Article ID 7606238 (16 pages); https://doi.org/10.1155/2019/7606238691501231885624
Search in Google Scholar Back to article
26. X. Yin, R. Zhang, C. Feng, J. Zhang, D. Liu, K. Xu, X. Wang, S. Zhang, Z. Li, X. Liu and H. Ma, Diallyl disulfide induces G2/M arrest and promotes apoptosis through the p53/p21 and MEK-ERK pathways in human esophageal squamous cell carcinoma, Oncol. Rep. 32(4) (2014) 1748–1756; https://doi.org/10.3892/or.2014.336125175641
Search in Google Scholar Back to article
27. M. Saleem, J. Asif, M. Asif and U. Saleem, Amygdalin from apricot kernels induces apoptosis and causes cell cycle arrest in cancer cells: an updated review, Anticancer Agents Med. Chem. 18(12) (2018) 1650–1655; https://doi.org/10.2174/187152061866618010516113629308747
Search in Google Scholar Back to article
28. Y. Li, Y. Zhou, M. Wang, X. Lin, Y. Zhang, I. Laurent, Y. Zhong and J. Li, Ampelopsin inhibits breast cancer cell growth through mitochondrial apoptosis pathway, Biol. Pharm. Bull. 44(11) (2021) 1738–1745; https://doi.org/10.1248/bpb.b21-0047034470980
Search in Google Scholar Back to article
29. M. B. Kastan and J. Bartek, Cell-cycle checkpoints and cancer, Nature 432 (2004) 316–323; https://doi.org/10.1038/nature0309715549093
Search in Google Scholar Back to article
30. Y. Sun, Y. Liu, X. Ma and H. Hu, The influence of cell cycle regulation on chemotherapy, Int. J. Mol. Sci. 22(13) (2021) Article ID 6923 (25 pages); https://doi.org/10.3390/ijms22136923826772734203270
Search in Google Scholar Back to article
31. V. M. Dirsch, D. S. Antlsperger, H. Hentze and A. M. Vollmar, Ajoene, an experimental anti-leukemic drug: mechanism of cell death, Leukemia 16 (2002) 74–83; https://doi.org/10.1038/sj.leu.240233711840266
Search in Google Scholar Back to article
32. S. Wullschleger, R. Loewith and M. N. Hall, TOR signaling in growth and metabolism, Cell 124(3) (2006) 471–484; https://doi.org/10.1016/j.cell.2006.01.01616469695
Search in Google Scholar Back to article
33. J. H. Kim, C. Xu, Y. S. Keum, B. Reddy, A. Conney and A. N. Kong, Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocya-nate and curcumin, Carcinogenesis 27(3) (2006) 475–482; https://doi.org/10.1093/carcin/bgi27216299382
Search in Google Scholar Back to article
34. R. Rong and X. Xijun, Erythropoietin pretreatment suppresses inflammation by activating the PI3K/Akt signaling pathway in myocardial ischemia-reperfusion injury, Exp. Ther. Med. 10(2) (2015) 413–418; https://doi.org/10.3892/etm.2015.2534450942326622330
Search in Google Scholar Back to article
35. G. Hoxhaj and B. D. Manning, The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolismo, Nat. Rev. Cancer 20 (2020) 74–88; https://doi.org/10.1038/s41568-019-0216-7731431231686003
Search in Google Scholar Back to article
36. N. Lamm, S. Rogers and A. J. Cesare, The mTOR pathway: implications for DNA replication, Prog. Biophys. Mol. Biol. 147 (2019) 17–25; https://doi.org/10.1016/j.pbiomolbio.2019.04.00230991055
Search in Google Scholar Back to article
37. L. Chen and H. Wang, Nicotine promotes human papillomavirus (HPV)-immortalized cervical epithelial cells (H8) proliferation by activating RPS27a-Mdm2-P53 pathway in vitro, Toxicol. Sci. 167(2) (2019) 408–418; https://doi.org/10.1093/toxsci/kfy24630272249
Search in Google Scholar Back to article
38. L. Liu, W. Michowski, A. Kolodziejczyk and P. Sicinski, The cell cycle in stem cell proliferation, pluripotency and differentiation, Nat. Cell Biol. 21 (2019) 1060–1067; https://doi.org/10.1038/s41556-019-0384-4706570731481793
Search in Google Scholar Back to article
39. H. K. Matthews, C. Bertoli and R. de Bruin, Cell cycle control in cancer, Nat. Rev. Mol. Cell Biol. 23 (2022) 74–88; https://doi.org/10.1038/s41580-021-00404-334508254
Search in Google Scholar Back to article
40. B. Xie, S. Wang, N. Jiang and J. J. Li, Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance, Cancer Lett. 443 (2019) 56–66; https://doi.org/10.1016/j.canlet.2018.11.019675906130481564
Search in Google Scholar Back to article
41. W. Lin, J. Xie, N. Xu, L. Huang, A. Xu, H. Li, C. Li, Y. Gao, M. Watanabe, C. Liu and P. Huang, Glaucocalyxin A induces G2/M cell cycle arrest and apoptosis through the PI3K/Akt pathway in human bladder cancer cells, Int. J. Biol. Sci. 14(4) (2018) 418–426; https://doi.org/10.7150/ijbs.23602593047429725263
Search in Google Scholar Back to article
42. M. Wasner, K. Tschöp, K. Spiesbach, U. Haugwitz, C. Johne, J. Mössner, R. Mantovani and K. Engeland, Cyclin B1 transcription is enhanced by the p300 coactivator and regulated during the cell cycle by a CHR-dependent repression mechanism, FEBS Lett. 536(1–3) (2003) 66–70; https://doi.org/10.1016/s0014-5793(03)00028-012586340
Search in Google Scholar Back to article
43. X. Q. Wang, C. M. Lo, L. Chen, E. S. Ngan, A. Xu and R. Y. Poon, CDK1-PDK1-PI3K/Akt signaling pathway regulates embryonic and induced pluripotency, Cell Death Differ. 24 (2017) 38–48; https://doi.org/10.1038/cdd.2016.84526050527636107
Search in Google Scholar Back to article

Ampelopsin induces MDA-MB-231 cell cycle arrest through cyclin B1-mediated PI3K/AKT/mTOR pathway in vitro and in vivo

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