Eupatorium lindleyanum DC. sesquiterpene fraction F1012-2 regulates p53/NF-κB signaling pathways in human breast cancer

Authors

  • Xinyu Wang College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China
  • Jiajin Xu College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China
  • Yixuan Tao College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China
  • Xiangrong Fan College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China
  • Xintong Shen College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China
  • Shasha Tian College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 311402, China

DOI:

https://doi.org/10.2298/ABS220630028W

Keywords:

Eupatorium lindleyanum DC., F1012-2, p53, Nuclear Factor-κB (NF-κB), triple-negative breast cancer

Abstract

Paper description:

  • F1012-2 is a novel sesquiterpene lactone isolated from the Chinese herbal medicine Eupatorium lindleyanum, whose regulation is ill-defined in breast cancer progression.
  • We investigated the anticancer activities of F1012-2 on human breast cancer and its effect on the crosstalk between p53 and NF-κB signaling pathways.
  • F1012-2 exhibited an inhibitory effect on triple-negative breast cancer (TNBC), and this is mainly related to the regulation of p53/NF-κB signaling pathways.
  • F1012-2 co-regulated p53 and NF-κB signaling pathways, thus providing multiple targets for therapeutic intervention in TNBC.

Abstract: F1012-2, a novel sesquiterpene lactone isolated from the Chinese herbal medicine Eupatorium lindleyanum DC, exhibits an antitumor effect. In this study, we investigated the anticancer activities of F1012-2 on ten human breast cancer lines and demonstrated significantly lower IC50 values for triple-negative breast cancer (TNBC) than for non-TNBC cell lines. The transcription factors p53 and nuclear factor-κB (NF-κB) are important regulators of tumorigenesis. F1012-2 not only depleted mutant p53, but also activated wild-type p53. F1012-2 reduced the expression of phosphorylated p65 and p105 NF-κB family members and coregulated p53, NF-κB members and their dependent targets. To further clarify the key role of p53, lentivirus small hairpin RNA (shRNA) infection was used to knockdown p53 in MDA-MB-231 cells. F1012-2 significantly reduced the inhibitory effect on cell proliferation and apoptosis, while the levels of p53, NF-κB family members and their dependent genes were not significantly different. F1012-2 exhibited a significant antitumor effect and reduced the expression of p53 in MDA-MB-231 xenografts. Taken together, our results show that F1012-2 exhibited an inhibitory effect on TNBC and affected the regulation of p53/NF-κB signaling pathways.

Downloads

Download data is not yet available.

References

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. https://doi.org/10.3322/caac.21708.

McCarthy AM, Friebel-Klingner T, Ehsan S, He W, Welch M, Chen J, Kontos D, Domchek SM, Conant EF, Semine A, Hughes K, Bardia A, Lehman C, Armstrong K. Relationship of established risk factors with breast cancer subtypes. Cancer Med. 2021;10(18):6456-67. https://doi.org/10.1002/cam4.4158.

Kwapisz D. Pembrolizumab and atezolizumab in triple-negative breast cancer. Cancer Immunol Immunother. 2021;70(3):607-17. https://doi.org/10.1007/s00262-020-02736-z.

Poma P. NF-κB and Disease. Int J Mol Sci. 2020;21(23):9181. https://doi.org/10.3390/ijms21239181.

Antonangeli F, Natalini A, Garassino MC, Sica A, Santoni A, Di Rosa F. Regulation of PD-L1 Expression by NF-κB in Cancer. Front Immunol. 2020;11:584626. https://doi.org/10.3389/fimmu.2020.584626.

Sargolzaei J, Etemadi T, Alyasin A. The P53/microRNA network: A potential tumor suppressor with a role in anticancer therapy. Pharmacol Res. 2020;160:105179. https://doi.org/10.1016/j.phrs.2020.105179.

Duffy MJ, Synnott NC, O'Grady S, Crown J. Targeting p53 for the treatment of cancer. Semin Cancer Biol. 2020;79:58-67. https://doi.org/10.1016/j.semcancer.2020.07.005.

Kollareddy M, Martinez LA. Distinct classes of flavonoids and epigallocatechin gallate, polyphenol affects an oncogenic mutant p53 protein, cell growth and invasion in a TNBC breast cancer cell line. Cells. 2021;10(4):797. https://doi.org/10.3390/cells10040797.

Carrà G, Lingua MF, Maffeo B, Taulli R, Morotti A. P53 vs NF-κB: the role of nuclear factor-kappa B in the regulation of p53 activity and vice versa. Cell Mol Life Sci. 2020;77(22):4449-58. https://doi.org/10.1007/s00018-020-03524-9.

Schneider G, Krämer OH. NFκB/p53 crosstalk-a promising new therapeutic target. Biochim Biophys Acta. 2011;1815(1):90-103. https://doi.org/10.1016/j.bbcan.2010.10.003.

Chu C, Yao S, Chen J, Wei X, Xia L, Chen D, Zhang J. Eupatorium lindleyanum DC flavonoids fraction attenuates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 2016;39:23-33. https://doi.org/10.1016/j.intimp.2016.06.032.

Li C, Chen S, Sha J, Cui J, He J, Fu J, Shen Y. Extraction and purification of total flavonoids from Eupatorium lindleyanum DC and evaluation of their antioxidant and enzyme inhibitory activities. Food Sci Nutr. 2021;9(5):2349-63. https://doi.org/10.1002/fsn3.1999.

Tian S, Chen Y, Yang B, Lou C, Zhu R, Zhao Y, Zhao H. F1012-2 inhibits the growth of triple negative breast cancer through induction of cell cycle arrest, apoptosis, and autophagy. Phytother Res. 2018;32(5):908-22. https://doi.org/10.1002/ptr.6030.

Dai L, Tian S, Zhang J, Lu M, Zhu J, Zhao H. F1012-2 Induced ROS-mediated DNA damage response through activation of MAPK pathway in triple-negative breast cancer. Biomed Res Int. 2021;2021:6650045. https://doi.org/10.1155/2021/6650045.

Zhu Z, Shen W, Tian S, Yang B, Zhao H. F3, a novel active fraction of Valeriana jatamansi Jones induces cell death via DNA damage in human breast cancer cells. Phytomedicine. 2019;57:245-54. https://doi.org/10.1016/j.phymed.2018.12.041.

Tian S, Jiang F, Zhang K, Zhu X, Jin B, Lu J, Ding Z. Flavonoids from the leaves of Carya cathayensis Sarg. inhibit vascular endothelial growth factor-induced angiogenesis. Fitoterapia. 2014;92:34-40. https://doi.org/10.1016/j.fitote.2013.09.016.

Kupper H, Storz H. Double staining technique using a combination of indirect and direct immunofluorescence with monoclonal antibodies. Acta Histochem. 1986;78(2):185-8. https://doi.org/10.1016/s0065-1281(86)80052-6.

Sasaki M, Nie L, Maki CG. MDM2 binding induces a conformational change in p53 that is opposed by heat-shock protein 90 and precedes p53 proteasomal degradation. J Biol Chem. 2007;282(19):14626-34. https://doi.org/10.1074/jbc.M610514200.

Duffy MJ, Synnott NC, Crown J. Mutant p53 in breast cancer: potential as a therapeutic target and biomarker. Breast Cancer Res Treat. 2018;170(2):213-9. https://doi.org/10.1007/s10549-018-4753-7.

Klein AM, Biderman L, Tong D, Alaghebandan B, Plumber SA, Mueller HS, van Vlimmeren A, Katz C, Prives C. MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53. Proc Natl Acad Sci USA. 2021;118(44):e2102420118. https://doi.org/10.1073/pnas.2102420118.

Fan Y, Mao R, Yang J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 2013;4(3):176-85. https://doi.org/10.1007/s13238-013-2084-3.

Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2(10):725-34. https://doi.org/10.1038/nri910.

Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011;12(8):695-708. https://doi.org/10.1038/ni.2065.

Dunphy G, Flannery SM, Almine JF, Connolly DJ, Paulus C, Jønsson KL, Jakobsen MR, Nevels MM, Bowie AG, Unterholzner L. Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signaling after nuclear DNA damage. Mol Cell. 2018;71(5):745-60.e5. https://doi.org/10.1016/j.molcel.2018.07.034.

Leibowitz B, Yu J. Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther. 2010;9(6):417-22. https://doi.org/10.4161/cbt.9.6.11392.

Lee TL, Yeh J, Friedman J, Yan B, Yang X, Yeh NT, Van Waes C, Chen Z. A signal network involving coactivated NF-kappaB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer. 2008;122(9):1987-98. https://doi.org/10.1002/ijc.23324.

Schneider G, Henrich A, Greiner G, Wolf V, Lovas A, Wieczorek M, Wagner T, Reichardt S, von Werder A, Schmid RM, Weih F, Heinzel T, Saur D, Krämer OH. Cross talk between stimulated NF-kappaB and the tumor suppressor p53. Oncogene. 2010;29(19):2795-806. https://doi.org/10.1038/onc.2010.46.

Wu X, Deng Y. Bax and BH3-domain-only proteins in p53-mediated apoptosis. Front Biosci. 2002;7:d151-6. https://doi.org/10.2741/a772.

Downloads

Published

2022-10-05

How to Cite

1.
Wang X, Xu J, Tao Y, Fan X, Shen X, Tian S. Eupatorium lindleyanum DC. sesquiterpene fraction F1012-2 regulates p53/NF-κB signaling pathways in human breast cancer. Arch Biol Sci [Internet]. 2022Oct.5 [cited 2024Nov.23];74(3):291-9. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/7883

Issue

Vol. 74 No. 3 (2022)

Section

Articles

License

Copyright (c) 2022 Xinyu Wang, Jiajin Xu, Yixuan Tao, Xiangrong Fan, Xintong Shen, Shasha Tian

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution 4.0 International License that allows others to share the work with an acknowledgment of the work’s authorship and initial publication in this journal.