Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Research Article

Diosmetin Induces Apoptosis by Downregulating AKT Phosphorylation via P53 Activation in Human Renal Carcinoma ACHN Cells

Author(s): Mingning Qiu, Jie Liu, Yongxia Su, Rong Guo, Baoyu Zhao* and Jianjun Liu*

Volume 27, Issue 10, 2020

Page: [1022 - 1028] Pages: 7

DOI: 10.2174/0929866527666200330172646

Price: $65

Abstract

Background: Diosmetin (DIOS) is the aglycone of the flavonoid glycoside, diosmin, derived naturally from the leaves of the legume, Olea europaea, and Acacia farnesiana. It has potent anticancer activity against multiple forms of cancers. However, the role of DIOS in renal carcinoma and its mechanism of action remain unclear.

Objective: The purpose of this study is to investigate the effect of DIOS on cell viability and apoptosis in renal carcinoma cells and explore the possible mechanism of action.

Methods: Cell viability, cytotoxicity, caspase activity, apoptosis, and expression of apoptotic related proteins were analyzed in renal carcinoma ACHN cells.

Results: The results showed that DIOS inhibited the cell viability, and induced cytotoxicity and apoptosis in ACHN cells. Furthermore, DIOS increased expression of p53 mRNA and proteins, and downregulated phosphorylation of the phosphoinositide 3-kinase and protein B kinase (PI3K/AKT). In addition, it was observed that the anticancer effect of DIOS was significantly enhanced by the p53 activator, but inhibited by the p53 inhibitor.

Conclusion: Our data suggested that DIOS induced apoptosis in renal carcinoma ACHN cells by reducing AKT phosphorylation through p53 upregulation.

Keywords: Diosmetin, apoptosis, p53, AKT phosphorylation, ACHN cells, renal carcinoma.

Graphical Abstract

[1]
Chan, B.C.; Ip, M.; Gong, H.; Lui, S.L.; See, R.H.; Jolivalt, C.; Fung, K.P.; Leung, P.C.; Reiner, N.E.; Lau, C.B. Synergistic effects of diosmetin with erythromycin against ABC transporter over-expressed methicillin-resistant Staphylococcus aureus (MRSA) RN4220/pUL5054 and inhibition of MRSA pyruvate kinase. Phytomedicine, 2013, 20(7), 611-614.
[2]
Yang, K.; Li, W.F.; Yu, J.F.; Yi, C.; Huang, W.F. Diosmetin protects against ischemia/reperfusion-induced acute kidney injury in mice. J. Surg. Res., 2017, 214, 69-78.
[http://dx.doi.org/10.1016/j.jss.2017.02.067] [PMID: 28624062]
[3]
Liu, Q.; Ci, X.; Wen, Z.; Peng, L. Diosmetin alleviates lipopolysaccharide-induced acute lung injury through activating the Nrf2 pathway and inhibiting the NLRP3 inflammasome. Biomol. Ther. (Seoul), 2018, 26(2), 157-166.
[http://dx.doi.org/10.4062/biomolther.2016.234] [PMID: 28365974]
[4]
Wang, C.; Liao, Y.; Wang, S.; Wang, D.; Wu, N.; Xu, Q.; Jiang, W.; Qiu, M.; Liu, C. Cytoprotective effects of diosmetin against hydrogen peroxide-induced L02 cell oxidative damage via activation of the Nrf2-ARE signaling pathway. Mol. Med. Rep., 2018, 17(5), 7331-7338.
[http://dx.doi.org/10.3892/mmr.2018.8750] [PMID: 29568961]
[5]
Shao, S.; Fu, F.; Wang, Z.; Song, F.; Li, C.; Wu, Z.X.; Ding, J.; Li, K.; Xiao, Y.; Su, Y.; Lin, X.; Yuan, G.; Zhao, J.; Liu, Q.; Xu, J. Diosmetin inhibits osteoclast formation and differentiation and prevents LPS-induced osteolysis in mice. J. Cell. Physiol., 2019, 234(8), 12701-12713.
[http://dx.doi.org/10.1002/jcp.27887] [PMID: 30515812]
[6]
Oak, C.; Khalifa, A.O.; Isali, I.; Bhaskaran, N.; Walker, E.; Shukla, S. Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. Int. J. Oncol., 2018, 53(2), 835-843.
[http://dx.doi.org/10.3892/ijo.2018.4407] [PMID: 29767250]
[7]
Choi, J.; Lee, D.H.; Park, S.Y.; Seol, J.W. Diosmetin inhibits tumor development and block tumor angiogenesis in skin cancer. Biomed. Pharmacother., 2019, 117109091.
[http://dx.doi.org/10.1016/j.biopha.2019.109091] [PMID: 31228803]
[8]
Liu, B.; Jia, K.; Yang, Y.; Hao, S.; Lu, C.; Xu, F.; Feng, D.; Zhu, R. Diosmetin induces cell apoptosis by regulating CYP1A1/CYP1A2 due to p53 activation in HepG2 cells. Protein Pept. Lett., 2017, 24(5), 406-412.
[http://dx.doi.org/10.2174/0929866524666170227123557] [PMID: 28245756]
[9]
Liu, J.; Wen, X.; Liu, B.; Zhang, Q.; Zhang, J.; Miao, H.; Zhu, R. Diosmetin inhibits the metastasis of hepatocellular carcinoma cells by downregulating the expression levels of MMP-2 and MMP-9. Mol. Med. Rep., 2016, 13(3), 2401-2408.
[http://dx.doi.org/10.3892/mmr.2016.4872] [PMID: 26847170]
[10]
Wang, C.; Li, S.; Ren, H.; Sheng, Y.; Wang, T.; Li, M.; Zhou, Q.; He, H.; Liu, C. anti-proliferation and pro-apoptotic effects of diosmetin via modulating cell cycle arrest and mitochondria-mediated intrinsic apoptotic pathway in MDA-MB-231 Cells. Med. Sci. Monit., 2019, 25, 4639-4647.
[http://dx.doi.org/10.12659/MSM.914058] [PMID: 31228347]
[11]
Xu, Z.; Yan, Y.; Xiao, L.; Dai, S.; Zeng, S.; Qian, L.; Wang, L.; Yang, X.; Xiao, Y.; Gong, Z. Radiosensitizing effect of diosmetin on radioresistant lung cancer cells via Akt signaling pathway. PLoS One, 2017, 12(4), e0175977.
[http://dx.doi.org/10.1371/journal.pone.0175977] [PMID: 28414793]
[12]
Chen, X.; Wu, Q.; Chen, Y.; Zhang, J.; Li, H.; Yang, Z.; Yang, Y.; Deng, Y.; Zhang, L.; Liu, B. Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition. Br. J. Pharmacol., 2019, 176(12), 2079-2094.
[http://dx.doi.org/10.1111/bph.14652] [PMID: 30825187]
[13]
Guo, H.; German, P.; Bai, S.; Barnes, S.; Guo, W.; Qi, X.; Lou, H.; Liang, J.; Jonasch, E.; Mills, G.B.; Ding, Z. The PI3K/AKT pathway and renal cell carcinoma. J. Genet. Genomics, 2015, 42(7), 343-353.
[http://dx.doi.org/10.1016/j.jgg.2015.03.003] [PMID: 26233890]
[14]
Walia, V.; Kakar, S.; Elble, R. Micromanagement of the mitochondrial apoptotic pathway by p53. Front. Biosci., 2011, 16, 749-758.
[http://dx.doi.org/10.2741/3717] [PMID: 21196200]
[15]
Bizzarri, M.; Proietti, S.; Cucina, A.; Reiter, R.J. Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: A review. Expert Opin. Ther. Targets, 2013, 17(12), 1483-1496.
[http://dx.doi.org/10.1517/14728222.2013.834890] [PMID: 24032643]
[16]
Suzuki, Y.; Tamura, G.; Satodate, R.; Fujioka, T. Infrequent mutation of p53 gene in human renal cell carcinoma detected by polymerase chain reaction single-strand conformation polymorphism analysis. Jpn. J. Cancer Res., 1992, 83(3), 233-235.
[http://dx.doi.org/10.1111/j.1349-7006.1992.tb00091.x] [PMID: 1582882]
[17]
Kochevar, J. Blockage of autonomous growth of ACHN cells by anti-renal cell carcinoma monoclonal antibody 5F4. Cancer Res., 1990, 50(10), 2968-2972.
[PMID: 2334900]
[18]
Miyake, H.; Hara, I.; Gohji, K.; Arakawa, S.; Kamidono, S. p53 modulation of Fas/Apo-1 mediated apoptosis in a human renal cell carcinoma cell line. Int. J. Oncol., 1998, 12(2), 469-473.
[http://dx.doi.org/10.3892/ijo.12.2.469] [PMID: 9458377]
[19]
Mantovani, F.; Collavin, L.; Del Sal, G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ., 2019, 26(2), 199-212.
[http://dx.doi.org/10.1038/s41418-018-0246-9] [PMID: 30538286]
[20]
Zhou, X.; Hao, Q.; Lu, H. Mutant p53 in cancer therapy-the barrier or the path. J. Mol. Cell Biol., 2019, 11(4), 293-305.
[http://dx.doi.org/10.1093/jmcb/mjy072] [PMID: 30508182]
[21]
Yamada, K.; Yoshida, K. Mechanical insights into the regulation of programmed cell death by p53 via mitochondria. Biochim. Biophys. Acta Mol. Cell Res., 2019, 1866(5), 839-848.
[http://dx.doi.org/10.1016/j.bbamcr.2019.02.009] [PMID: 30790591]
[22]
Hafner, A.; Bulyk, M.L.; Jambhekar, A.; Lahav, G. The multiple mechanisms that regulate p53 activity and cell fate. Nat. Rev. Mol. Cell Biol., 2019, 20(4), 199-210.
[http://dx.doi.org/10.1038/s41580-019-0110-x] [PMID: 30824861]
[23]
Issaeva, N.; Bozko, P.; Enge, M.; Protopopova, M.; Verhoef, L.G.; Masucci, M.; Pramanik, A.; Selivanova, G. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat. Med., 2004, 10(12), 1321-1328.
[http://dx.doi.org/10.1038/nm1146] [PMID: 15558054]
[24]
Gudkov, A.V.; Komarova, E.A. Prospective therapeutic applications of p53 inhibitors. Biochem. Biophys. Res. Commun., 2005, 331(3), 726-736.
[http://dx.doi.org/ 10.1016/j.bbrc. 2005.03.153] [PMID: 15865929]
[25]
Zhong, W.F.; Wang, X.H.; Pan, B.; Li, F.; Kuang, L.; Su, Z.X. Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways. Oncol. Lett., 2016, 12(4), 2894-2899.
[http://dx.doi.org/ 10.3892/ol.2016.4989] [PMID: 27698876]
[26]
Zhang, C.; Li, X.Y.; Luo, Z.Z.; Wu, T.W.; Hu, H. Upregulation of LINC00982 inhibits cell proliferation and promotes cell apoptosis by regulating the activity of PI3K/AKT signaling pathway in renal cancer. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(4), 1443-1450.
[PMID: 30840265]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy