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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Corilagin Inhibits Esophageal Squamous Cell Carcinoma by Inducing DNA Damage and Down-Regulation of RNF8

Author(s): Fanghua Qiu, Lifang Liu, Yu Lin, Zetian Yang and Feng Qiu*

Volume 19, Issue 8, 2019

Page: [1021 - 1028] Pages: 8

DOI: 10.2174/1871520619666190307120811

Price: $65


Background: Esophageal squamous cell carcinoma (ESCC), the most prevalent histologic subtype of esophageal cancer, is an aggressive malignancy with poor prognosis and a high incidence in the East. Corilagin, an active component present in Phyllanthus niruri L., has been shown to suppress tumor growth in various cancers. However, the effects of corilagin on ESCC and the mechanisms for its tumor suppressive function remain unknown.

Methods: Cell proliferation was measured by Cell Counting Kit-8 assay and colony formation assays. Annexin V/PI double-staining was performed to assess cell apoptosis. Immunofluorescence staining and western blotting were used to evaluate the protein expression. A xenograft mice model was used to assess the in vivo antitumor effects of corilagin alone or in combination with cisplatin.

Results: We for the first time showed that corilagin was effectively able to inhibit ESCC cell proliferation and induce cell apoptosis. Additionally, our results validated its antitumor effects in vivo using a xenograft mouse model. Mechanistically, we found that corilagin caused significant DNA damage in ESCC cells. We found that corilagin could significantly attenuate the expression of the E3 ubiquitin ligase RING finger protein 8 (RNF8) through ubiquitin-proteasome pathway, leading to the inability of DNA damage repair response and eventually causing cell apoptosis. Furthermore, we also showed that corilagin substantially enhanced the antitumor effects of chemotherapy drug cisplatin both in vitro and in vivo.

Conclusion: Our results not only provided novel and previously unrecognized evidences for corilagin-induced tumor suppression through inducing DNA damage and targeting RNF8 in ESCC, but also highlighted that corilagin might serve as an adjunctive treatment to conventional chemotherapeutic drugs in ESCC patients.

Keywords: Corilagin, RNF8, DNA damage, esophageal squamous cell carcinoma, cisplatin, chemosensitivity.

Graphical Abstract
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68, 7-30.
Pennathur, A.; Gibson, M.K.; Jobe, B.A.; Luketich, J.D. Oesophageal carcinoma. Lancet, 2013, 381, 400-412.
Arnal, D.M.J.; Ferrandez Arenas, A.; Lanas Arbeloa, A. Esophageal cancer: Risk factors, screening and endoscopic treatment in western and eastern countries. World J. Gastroenterol., 2015, 21, 7933-7943.
Adenis, A.; Robb, W.B.; Mariette, C. Esophageal carcinoma. N. Engl. J. Med., 2015, 372, 1471.
Alsop, B.R.; Sharma, P. Esophageal cancer. Gastroenterol. Clin. North Am., 2016, 45, 399-412.
Kaur, N.; Kaur, B.; Sirhindi, G. Phytochemistry and pharmacology of phyllanthus niruri L.: A review. Phytother. Res., 2017, 31, 980-1004.
Lee, N.Y.; Khoo, W.K.; Adnan, M.A.; Mahalingam, T.P.; Fernandez, A.R.; Jeevaratnam, K. The pharmacological potential of Phyllanthus niruri. J. Pharm. Pharmacol., 2016, 68, 953-969.
Zheng, Z.Z.; Chen, L.H.; Liu, S.S.; Deng, Y.; Zheng, G.H.; Gu, Y.; Ming, Y.L. Bio-guided fraction and isolation of the antitumor components from phyllanthus niruri L. BioMed Res. Int., 2016, 2016, 9729275.
Jia, L.; Jin, H.; Zhou, J.; Chen, L.; Lu, Y.; Ming, Y.; Yu, Y. A potential anti-tumor herbal medicine, Corilagin, inhibits ovarian cancer cell growth through blocking the TGF-beta signaling pathways. BMC Complement. Altern. Med., 2013, 13, 33.
Jia, L.; Zhou, J.; Zhao, H.; Jin, H.; Lv, M.; Zhao, N.; Zheng, Z.; Lu, Y.; Ming, Y.; Yu, Y. Corilagin sensitizes epithelial ovarian cancer to chemotherapy by inhibiting snailglycolysis pathways. Oncol. Rep., 2017, 38, 2464-2470.
Gu, Y.; Xiao, L.; Ming, Y.; Zheng, Z.; Li, W. Corilagin suppresses cholangiocarcinoma progression through notch signaling pathway in vitro and in vivo. Int. J. Oncol., 2016, 48, 1868-1876.
Li, X.; Deng, Y.; Zheng, Z.; Huang, W.; Chen, L.; Tong, Q.; Ming, Y. Corilagin, a promising medicinal herbal agent. Biomed. Pharmacother., 2018, 99, 43-50.
Kasparek, T.R.; Humphrey, T.C. DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin. Cell Dev. Biol., 2011, 22, 886-897.
Mahaney, B.L.; Meek, K.; Lees-Miller, S.P. Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem. J., 2009, 417, 639-650.
Rocha, J.C.; Busatto, F.F.; Guecheva, T.N.; Saffi, J. Role of nucleotide excision repair proteins in response to DNA damage induced by topoisomerase II inhibitors. Mutat. Res. Rev. Mutat. Res., 2016, 768, 68-77.
Nakada, S.; Yonamine, R.M.; Matsuo, K. RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1. Cancer Res., 2012, 72, 4974-4983.
Thorslund, T.; Ripplinger, A.; Hoffmann, S.; Wild, T.; Uckelmann, M.; Villumsen, B.; Narita, T.; Sixma, T.K.; Choudhary, C.; Bekker-Jensen, S.; Mailand, N. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature, 2015, 527, 389-393.
Huen, M.S.; Grant, R.; Manke, I.; Minn, K.; Yu, X.; Yaffe, M.B.; Chen, J. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell, 2007, 131, 901-914.
Feng, L.; Chen, J. The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat. Struct. Mol. Biol., 2012, 19, 201-206.
Huang, J.; Huen, M.S.; Kim, H.; Leung, C.C.; Glover, J.N.
Yu, X.; Chen, J. RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nat. Cell Biol., 2009, 11, 592-603.
Zamble, D.B.; Lippard, S.J. Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem. Sci., 1995, 20, 435-439.
Hecht, S.M.; Berry, D.E.; MacKenzie, L.J.; Busby, R.W.; Nasuti, C.A. A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I. J. Nat. Prod., 1992, 55, 401-413.
Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70, 369-413.
Bekker-Jensen, S.; Mailand, N. The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. FEBS Lett., 2011, 585, 2914-2919.
Kwon, Y.T.; Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci., 2017, 42, 873-886.
Goldstein, M.; Kastan, M.B. The DNA damage response: Implications for tumor responses to radiation and chemotherapy. Annu. Rev. Med., 2015, 66, 129-143.
Khanna, A. DNA damage in cancer therapeutics: A boon or a curse? Cancer Res., 2015, 75, 2133-2138.
Zheng, H.C. The molecular mechanisms of chemoresistance in cancers. Oncotarget, 2017, 8, 59950-59964.
Lee, H.J.; Li, C.F.; Ruan, D.; Powers, S.; Thompson, P.A.; Frohman, M.A.; Chan, C.H. The DNA damage transducer RNF8 facilitates cancer chemoresistance and progression through twist activation. Mol. Cell, 2016, 63, 1021-1033.

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