Anticancer Effect of Dihydroartemisinin via Dual Control of ROS-induced Apoptosis and Protective Autophagy in Prostate Cancer 22Rv1 Cells


Citar

Texto integral

Resumo

Background:Dihydroartemisinin (DHA), a natural agent, exhibits potent anticancer activity. However, its biological activity on prostate cancer (PCa) 22Rv1 cells has not been previously investigated.

Objective:In this study, we demonstrate that DHA induces anticancer effects through the induction of apoptosis and autophagy.

Methods:Cell viability and proliferation rate were assessed using the CCK-8 assay and cell clone formation assay. The generation of reactive oxygen species (ROS) was detected by flow cytometry. The molecular mechanism of DHA-induced apoptosis and autophagy was examined using Western blot and RT-qPCR. The formation of autophagosomes and the changes in autophagy flux were observed using transmission electron microscopy (TEM) and confocal microscopy. The effect of DHA combined with Chloroquine (CQ) was assessed using the EdU assay and flow cytometry. The expressions of ROS/AMPK/mTOR-related proteins were detected using Western blot. The interaction between Beclin-1 and Bcl-2 was examined using Co-IP.

Results:DHA inhibited 22Rv1 cell proliferation and induced apoptosis. DHA exerted its antiprostate cancer effects by increasing ROS levels. DHA promoted autophagy progression in 22Rv1 cells. Inhibition of autophagy enhanced the pro-apoptotic effect of DHA. DHA-induced autophagy initiation depended on the ROS/AMPK/mTOR pathway. After DHA treatment, the impact of Beclin- 1 on Bcl-2 was weakened, and its binding with Vps34 was enhanced.

Conclusion:DHA induces apoptosis and autophagy in 22Rv1 cells. The underlying mechanism may involve the regulation of ROS/AMPK/mTOR signaling pathways and the interaction between Beclin-1 and Bcl-2 proteins. Additionally, the combination of DHA and CQ may enhance the efficacy of DHA in inhibiting tumor cell activity.

Sobre autores

Jiaxin Yang

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Email: info@benthamscience.net

Tong Xia

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Email: info@benthamscience.net

Sijie Zhou

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Email: info@benthamscience.net

Sihao Liu

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Email: info@benthamscience.net

Tingyu Pan

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Email: info@benthamscience.net

Ying Li

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Email: info@benthamscience.net

Ziguo Luo

Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University

Autor responsável pela correspondência
Email: info@benthamscience.net

Bibliografia

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  2. Culp, M.B.; Soerjomataram, I.; Efstathiou, J.A.; Bray, F.; Jemal, A. Recent global patterns in prostate cancer incidence and mortality rates. Eur. Urol., 2020, 77(1), 38-52. doi: 10.1016/j.eururo.2019.08.005 PMID: 31493960
  3. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin., 2022, 72(1), 7-33. doi: 10.3322/caac.21708 PMID: 35020204
  4. Wang, L.; Lu, B.; He, M.; Wang, Y.; Wang, Z.; Du, L. Prostate cancer incidence and mortality: Global status and temporal trends in 89 Countries From 2000 to 2019. Front. Public Health, 2022, 10, 811044. doi: 10.3389/fpubh.2022.811044 PMID: 35252092
  5. Zhu, Y.; Mo, M.; Wei, Y.; Wu, J.; Pan, J.; Freedland, S.J.; Zheng, Y.; Ye, D. Epidemiology and genomics of prostate cancer in Asian men. Nat. Rev. Urol., 2021, 18(5), 282-301. doi: 10.1038/s41585-021-00442-8 PMID: 33692499
  6. Qiu, Y.; Xu, J. Current opinion and mechanistic interpretation of combination therapy for castration-resistant prostate cancer. Asian J. Androl., 2019, 21(3), 270-278. doi: 10.4103/aja.aja_10_19 PMID: 30924449
  7. Ma, Q.; Liao, H.; Xu, L.; Li, Q.; Zou, J.; Sun, R.; Xiao, D.; Liu, C.; Pu, W.; Cheng, J.; Zhou, X.; Huang, G.; Yao, L.; Zhong, X.; Guo, X. Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin. Chin. Med., 2020, 15(1), 37. doi: 10.1186/s13020-020-00318-w PMID: 32351616
  8. Qu, C.; Ma, J.; Liu, X.; Xue, Y.; Zheng, J.; Liu, L.; Liu, J.; Li, Z.; Zhang, L.; Liu, Y. Dihydroartemisinin exerts anti-tumor activity by inducing mitochondrion and endoplasmic reticulum apoptosis and autophagic cell death in human glioblastoma cells. Front. Cell. Neurosci., 2017, 11, 310. doi: 10.3389/fncel.2017.00310 PMID: 29033794
  9. Paccez, J.D.; Duncan, K.; Sekar, D.; Correa, R.G.; Wang, Y.; Gu, X.; Bashin, M.; Chibale, K.; Libermann, T.A.; Zerbini, L.F. Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl. Oncogenesis, 2019, 8(3), 14. doi: 10.1038/s41389-019-0122-6 PMID: 30783079
  10. Wong, K.H.; Yang, D.; Chen, S.; He, C.; Chen, M. Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review. Asian J. Pharmaceut. Sci., 2022, 17(4), 475-490. doi: 10.1016/j.ajps.2022.04.005 PMID: 36105316
  11. Li, X.; He, S.; Ma, B. Autophagy and autophagy-related proteins in cancer. Mol. Cancer, 2020, 19(1), 12. doi: 10.1186/s12943-020-1138-4 PMID: 31969156
  12. Wang, L.; Li, J.; Shi, X.; Li, S.; Tang, P.M.K.; Li, Z.; Li, H.; Wei, C. Antimalarial dihydroartemisinin triggers autophagy within HeLa cells of human cervical cancer through Bcl-2 phosphorylation at Ser70. Phytomedicine, 2019, 52, 147-156. doi: 10.1016/j.phymed.2018.09.221 PMID: 30599894
  13. Liu, X.; Wu, J.; Fan, M.; Shen, C.; Dai, W.; Bao, Y.; Liu, J.H.; Yu, B.Y. Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells. Cell Death Dis., 2018, 9(11), 1048. doi: 10.1038/s41419-018-1006-y PMID: 30323180
  14. Shi, X.; Li, S.; Wang, L.; Li, H.; Li, Z.; Wang, W.; Bai, J.; Sun, Y.; Li, J.; Li, X. RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human laryngeal squamous cell carcinoma. Chin. Med., 2020, 15(1), 64. doi: 10.1186/s13020-020-00340-y PMID: 32577124
  15. Li, M.; Zhu, X.; Zhao, B.; Shi, L.; Wang, W.; Hu, W.; Qin, S.; Chen, B.; Zhou, P.; Qiu, B.; Gao, Y.; Liu, B. Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS–AMPK–mTOR axis. Cell Death Dis., 2019, 10(7), 489. doi: 10.1038/s41419-019-1728-5 PMID: 31222000
  16. Mei, Y.; Glover, K.; Su, M.; Sinha, S.C. Conformational flexibility of BECN1: Essential to its key role in autophagy and beyond. Protein Sci., 2016, 25(10), 1767-1785. doi: 10.1002/pro.2984 PMID: 27414988
  17. Dai, X.; Zhang, X.; Chen, W.; Chen, Y.; Zhang, Q.; Mo, S.; Lu, J. Dihydroartemisinin: A potential natural anticancer drug. Int. J. Biol. Sci., 2021, 17(2), 603-622. doi: 10.7150/ijbs.50364 PMID: 33613116
  18. Du, S.; Xu, G.; Zou, W.; Xiang, T.; Luo, Z. Effect of dihydroartemisinin on UHRF1 gene expression in human prostate cancer PC-3 cells. Anticancer Drugs, 2017, 28(4), 384-391. doi: 10.1097/CAD.0000000000000469 PMID: 28059831
  19. Xia, T.; Liu, S.; Xu, G.; Zhou, S.; Luo, Z. Dihydroartemisinin induces cell apoptosis through repression of UHRF1 in prostate cancer cells. Anticancer Drugs, 2022, 33(1), e113-e124. doi: 10.1097/CAD.0000000000001156 PMID: 34387595
  20. Du, X.X.; Li, Y.J.; Wu, C.L.; Zhou, J.H.; Han, Y.; Sui, H.; Wei, X.L.; Liu, L.; Huang, P.; Yuan, H.H.; Zhang, T.T.; Zhang, W.J.; Xie, R.; Lang, X.H.; Jia, D.X.; Bai, Y.X. Initiation of apoptosis, cell cycle arrest and autophagy of esophageal cancer cells by dihydroartemisinin. Biomed. Pharmacother., 2013, 67(5), 417-424. doi: 10.1016/j.biopha.2013.01.013 PMID: 23582790
  21. Jia, G.; Kong, R.; Ma, Z.B.; Han, B.; Wang, Y.W.; Pan, S.H.; Li, Y.H.; Sun, B. The activation of c-Jun NH2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells. J. Exp. Clin. Cancer Res., 2014, 33(1), 8. doi: 10.1186/1756-9966-33-8 PMID: 24438216
  22. Fu, X.Y.; Yang, B.Y.; Yin, F.L. The role and molecular mechanism of autophagy in the development of prostate cancer. Zhonghua Yi Xue Za Zhi, 2018, 98(32), 2537-2540. doi: 10.3760/cma.j.issn.0376-2491.2018.32.001 PMID: 30220136
  23. Zhang, J.; Wang, G.; Zhou, Y.; Chen, Y.; Ouyang, L.; Liu, B. Mechanisms of autophagy and relevant small-molecule compounds for targeted cancer therapy. Cell. Mol. Life Sci., 2018, 75(10), 1803-1826. doi: 10.1007/s00018-018-2759-2 PMID: 29417176
  24. Kimmelman, A.C.; White, E. Autophagy and tumor metabolism. Cell Metab., 2017, 25(5), 1037-1043. doi: 10.1016/j.cmet.2017.04.004 PMID: 28467923
  25. Amaravadi, R.K.; Kimmelman, A.C.; Debnath, J. Targeting autophagy in cancer: Recent advances and future directions. Cancer Discov., 2019, 9(9), 1167-1181. doi: 10.1158/2159-8290.CD-19-0292 PMID: 31434711
  26. Tang, T.; Xia, Q.J.; Xi, M.R. Dihydroartemisinin and its anticancer activity against endometrial carcinoma and cervical cancer: Involvement of apoptosis, autophagy and transferrin receptor. Singapore Med. J., 2021, 62(2), 96-103. doi: 10.11622/smedj.2019138 PMID: 31680182
  27. Bhaw-Luximon, A.; Jhurry, D. Artemisinin and its derivatives in cancer therapy: Status of progress, mechanism of action, and future perspectives. Cancer Chemother. Pharmacol., 2017, 79(3), 451-466. doi: 10.1007/s00280-017-3251-7 PMID: 28210763
  28. Prasad, S.; Gupta, S.C.; Tyagi, A.K. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett., 2017, 387, 95-105. doi: 10.1016/j.canlet.2016.03.042 PMID: 27037062
  29. Kocak, M.; Ezazi Erdi, S.; Jorba, G.; Maestro, I.; Farrés, J.; Kirkin, V.; Martinez, A.; Pless, O. Targeting autophagy in disease: Established and new strategies. Autophagy, 2022, 18(3), 473-495. doi: 10.1080/15548627.2021.1936359 PMID: 34241570
  30. Du, W.; Pang, C.; Xue, Y.; Zhang, Q.; Wei, X. Dihydroartemisinin inhibits the Raf/ERK/MEK and PI3K/AKT pathways in glioma cells. Oncol. Lett., 2015, 10(5), 3266-3270. doi: 10.3892/ol.2015.3699 PMID: 26722323
  31. Handrick, R.; Ontikatze, T.; Bauer, K.D.; Freier, F.; Rübel, A.; Dürig, J.; Belka, C.; Jendrossek, V. Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathway. Mol. Cancer Ther., 2010, 9(9), 2497-2510. doi: 10.1158/1535-7163.MCT-10-0051 PMID: 20663933
  32. Liu, Q.; Zhou, X.; Li, C.; Zhang, X.; Li, C. Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK. Oncol. Lett., 2018, 15(4), 5781-5786. doi: 10.3892/ol.2018.8013 PMID: 29545903
  33. Shi, X.; Wang, L.; Ren, L.; Li, J.; Li, S.; Cui, Q.; Li, S. Dihydroartemisinin, an antimalarial drug, induces absent in melanoma 2 inflammasome activation and autophagy in human hepatocellular carcinoma HepG2215 cells. Phytother. Res., 2019, 33(5), 1413-1425. doi: 10.1002/ptr.6332 PMID: 30873702
  34. Chen, S.S.; Hu, W.; Wang, Z.; Lou, X.E.; Zhou, H.J. p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy. Cancer Biol. Ther., 2015, 16(5), 770-779. doi: 10.1080/15384047.2015.1026477 PMID: 25891535
  35. El-Baba, C.; Baassiri, A.; Kiriako, G.; Dia, B.; Fadlallah, S.; Moodad, S.; Darwiche, N. Terpenoids’ anti-cancer effects: Focus on autophagy. Apoptosis, 2021, 26(9-10), 491-511. doi: 10.1007/s10495-021-01684-y PMID: 34269920

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML
Baixar

Declaração de direitos autorais © Bentham Science Publishers, 2024