Open Access

hERG1 is involved in the pathophysiological process and inhibited by berberine in SKOV3 cells

  • Authors:
    • Duo Zhi
    • Kun Zhou
    • Dahai Yu
    • Xiaofan Fan
    • Juan Zhang
    • Xiang Li
    • Mei Dong
  • View Affiliations

  • Published online on: April 17, 2019     https://doi.org/10.3892/ol.2019.10263
  • Pages: 5653-5661
  • Copyright: © Zhi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The human ether‑a‑go‑go‑related potassium channel 1 (hERG1) is a functional component of the voltage‑gated Kv11.1 potassium channel, which is commonly described as a crucial factor in the tumorigenesis of a variety of tumors. Ovarian cancer is one of the most severe types of cancer, with an extremely poor prognosis. Advances have been made in recent years; however, drug resistance and tumor recurrence remain critical issues underlying satisfactory treatment outcomes. Therefore, more effective antitumor agents with low levels of drug resistance for ovarian cancer treatment are urgently required in clinical practice. In the present study, hERG1 mRNA expression in ovarian tumor tissues and cell lines were measured by reverse transcription‑quantitative polymerase chain reaction. Immunohistochemistry and western blotting were used to assess the expression levels of hERG1 protein. Cell proliferation, migration and invasion were assessed by Cell Counting Kit‑8 assay and Transwell assay. A tumor xenograft assay was used to determine the growth of tumors in vivo. It was demonstrated that the expression levels of hERG1 were significantly elevated in ovarian cancer tissues and expressed in ovarian cancer cell lines, particularly in SKOV3 cells. Abnormal hERG1 expression was significantly associated with the proliferation, migration and invasion abilities of ovarian cancer. In addition, berberine (BBR) may be used as a potential drug in the treatment of ovarian cancer, possibly due to its inhibitory effects on the hERG1 channels. In conclusion, the present study demonstrated that hERG1 may be a potential therapeutic target in the treatment of ovarian cancer and provided novel insights into the mechanism underlying the antitumor effects of BBR in ovarian cancer.

References

1 

Wright JD, Chen L, Hou JY, Burke WM, Tergas AI, Ananth CV, Neugut AI and Hershman DL: Association of hospital volume and quality of care with survival for ovarian cancer. Obstet Gynecol. 130:545–553. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Lee YK, Chung HH, Kim JW, Song YS and Park NH: Expression of phosphorylated Akt and hTERT is associated with prognosis of epithelial ovarian carcinoma. Int J Clin Exp Pathol. 8:14971–14976. 2015.PubMed/NCBI

3 

Stefanou DT, Bamias A, Episkopou H, Kyrtopoulos SA, Likka M, Kalampokas T, Photiou S, Gavalas N, Sfikakis PP, Dimopoulos MA and Souliotis VL: Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer. PLoS One. 10:e01176542015. View Article : Google Scholar : PubMed/NCBI

4 

Bandera EV, Lee VS, Qin B, Rodriguez-Rodriguez L, Powell CB and Kushi LH: Impact of body mass index on ovarian cancer survival varies by stage. Br J Cancer. 117:282–289. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Littleton JT and Ganetzky B: Ion channels and synaptic organization: Analysis of the Drosophila genome. Neuron. 26:35–43. 2000. View Article : Google Scholar : PubMed/NCBI

6 

Curran ME: Potassium ion channels and human disease: Phenotypes to drug targets? Curr Opin Biotechnol. 9:565–572. 1998. View Article : Google Scholar : PubMed/NCBI

7 

Ji CD, Wang YX, Xiang DF, Liu Q, Zhou ZH, Qian F, Yang L, Ren Y, Cui W, Xu SL, et al: Kir2.1 interaction with Stk38 promotes invasion and metastasis of human gastric cancer by enhancing MEKK2-MEK1/2-ERK1/2 signaling. Cancer Res. 78:3041–3053. 2018. View Article : Google Scholar : PubMed/NCBI

8 

Cheng YY, Wright CM, Kirschner MB, Williams M, Sarun KH, Sytnyk V, Leshchynska I, Edelman JJ, Vallely MP, McCaughan BC, et al: KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma. Mol Cancer. 15:442016. View Article : Google Scholar : PubMed/NCBI

9 

Lastraioli E, Lottini T, Bencini L, Bernini M and Arcangeli A: hERG1 potassium channels: Novel biomarkers in human solid cancers. Biomed Res Int. 2015:8964322015. View Article : Google Scholar : PubMed/NCBI

10 

Patanè S: HERG-targeted therapy in both cancer and cardiovascular system with cardiovascular drugs. Int J Cardiol. 176:1082–1085. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Leanza L, Biasutto L, Managò A, Gulbins E, Zoratti M and Szabò I: Intracellular ion channels and cancer. Front Physiol. 4:2272013. View Article : Google Scholar : PubMed/NCBI

12 

García-Quiroz J, García-Becerra R, Santos-Martínez N, Barrera D, Ordaz-Rosado D, Avila E, Halhali A, Villanueva O, Ibarra-Sánchez MJ, Esparza-López J, et al: In vivo dual targeting of the oncogenic Ether-à-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors. BMC Cancer. 14:7452014. View Article : Google Scholar : PubMed/NCBI

13 

D'Amico M, Gasparoli L and Arcangeli A: Potassium channels: Novel emerging biomarkers and targets for therapy in cancer. Recent Pat Anticancer Drug Discov. 8:53–65. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Balijepalli SY, Lim E, Concannon SP, Chew CL, Holzem KE, Tester DJ, Ackerman MJ, Delisle BP, Balijepalli RC and January CT: Mechanism of loss of Kv11.1 K+ current in mutant T421M-Kv11.1-expressing rat ventricular myocytes: Interaction of trafficking and gating. Circulation. 126:2809–2818. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Fortunato A: The role of hERG1 ion channels in epithelial-mesenchymal transition and the capacity of riluzole to reduce cisplatin resistance in colorectal cancer cells. Cell Oncol (Dordr). 40:367–378. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Becchetti A, Crescioli S, Zanieri F, Petroni G, Mercatelli R, Coppola S, Gasparoli L, D'Amico M, Pillozzi S, Crociani O, et al: The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression. Sci Signal. 10(pii): eaaf32362017. View Article : Google Scholar : PubMed/NCBI

17 

Sundby E, Han J, Kaspersen SJ and Hoff BH: In vitro baselining of new pyrrolopyrimidine EGFR-TK inhibitors with Erlotinib. Eur J Pharm Sci. 80:56–65. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Fraley ME, Garbaccio RM, Arrington KL, Hoffman WF, Tasber ES, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Fernandes C, et al: Kinesin spindle protein (KSP) inhibitors. Part 2: The design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP. Bioorg Med Chem Lett. 16:1775–1779. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Gao J, Wang G, Wu J, Zuo Y, Zhang J and Chen J: Arsenic trioxide inhibits Skp2 expression to increase chemosensitivity to gemcitabine in pancreatic cancer cells. Am J Transl Res. 11:991–997. 2019.PubMed/NCBI

20 

Qu X, Wang F, Zhang Y, Du Z, Ren J, Liu Z and Zhang L: Biocompatible heterogeneous MOF-Cu catalyst used for in vivo drug synthesis at targeted subcellular organelles. Angew Chem Int Ed Engl. 19–Mar;2019.(Epub ahead of print). doi org/10.1002/anie.201901760.

21 

Park HH, Choi SW, Lee GJ, Kim YD, Noh HJ, Oh SJ, Yoo I, Ha YJ, Koo GB, Hong SS, et al: A formulated red ginseng extract inhibits autophagic flux and sensitizes to doxorubicin-induced cell death. J Ginseng Res. 43:86–94. 2019. View Article : Google Scholar : PubMed/NCBI

22 

Zhi D, Feng PF, Sun JL, Guo F, Zhang R, Zhao X and Li BX: The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides. Eur J Pharm Sci. 76:149–155. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Ortiz LM, Lombardi P, Tillhon M and Scovassi AI: Berberine, an epiphany against cancer. Molecules. 19:12349–12367. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Ayati SH, Fazeli B, Momtazi-Borojeni AA, Cicero AFG, Pirro M and Sahebkar A: Regulatory effects of berberine on microRNome in cancer and other conditions. Crit Rev Oncol Hematol. 116:147–158. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Wang J, Yang S, Cai X, Dong J, Chen Z, Wang R, Zhang S, Cao H, Lu D, Jin T, et al: Berberine inhibits EGFR signaling and enhances the antitumor effects of EGFR inhibitors in gastric cancer. Oncotarget. 7:76076–76086. 2016.PubMed/NCBI

26 

Wang H, Li K, Ma L, Wu S, Hu J, Yan H, Jiang J and Li Y: Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy. Virol J. 14:22017. View Article : Google Scholar : PubMed/NCBI

27 

Puthdee N, Seubwai W, Vaeteewoottacharn K, Boonmars T, Cha'on U, Phoomak C and Wongkham S: Berberine induces cell cycle arrest in cholangiocarcinoma cell lines via inhibition of NF-κB and STAT3 pathways. Biol Pharm Bull. 40:751–757. 2017. View Article : Google Scholar : PubMed/NCBI

28 

Hsu WH, Hsieh YS, Kuo HC, Teng CY, Huang HI, Wang CJ, Yang SF, Liou YS and Kuo WH: Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL. Arch Toxicol. 81:719–728. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Xing Y, Ding T, Wang Z, Wang L, Guan H, Tang J, Mo D and Zhang J: Temporally-controlled photothermal/photodynamic and combined therapy for overcoming multidrug resistance of cancer by polydopamine nanoclustered micelles. ACS Appl Mater Interfaces. 2–Apr;2019.(Epub ahead of print). doi: 10.1021/acsami.9b00472. View Article : Google Scholar

30 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Capriglione S, Luvero D, Plotti F, Terranova C, Montera R, Scaletta G, Schirò T, Rossini G, Benedetti Panici P and Angioli R: Ovarian cancer recurrence and early detection: May HE4 play a key role in this open challenge? A systematic review of literature. Med Oncol. 34:1642017. View Article : Google Scholar : PubMed/NCBI

32 

Yi H, Zheng X, Song J, Shen R, Su Y and Lin D: Exosomes mediated pentose phosphate pathway in ovarian cancer metastasis: A proteomics analysis. Int J Clin Exp Pathol. 8:15719–15728. 2015.PubMed/NCBI

33 

Zheng F, Wu J, Tang Q, Xiao Q, Wu W and Hann SS: The enhancement of combination of berberine and metformin in inhibition of DNMT1 gene expression through interplay of SP1 and PDPK1. J Cell Mol Med. 22:600–612. 2018. View Article : Google Scholar : PubMed/NCBI

34 

Wang X, Wang N, Li H, Liu M, Cao F, Yu X, Zhang J, Tan Y, Xiang L and Feng Y: Up-regulation of PAI-1 and down-regulation of uPA are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine. Int J Mol Sci. 17:5772016. View Article : Google Scholar : PubMed/NCBI

35 

Li D, Zhang Y, Liu K, Zhao Y, Xu B, Xu L, Tan L, Tian Y, Li C, Zhang W, et al: Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth. Lab Invest. 97:1343–1353. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Chu SC, Yu CC, Hsu LS, Chen KS, Su MY and Chen PN: Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells. Mol Pharmacol. 86:609–623. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Liu X, Ji Q, Ye N, Sui H, Zhou L, Zhu H, Fan Z, Cai J and Li Q: Berberine inhibits invasion and metastasis of colorectal cancer cells via COX-2/PGE2 mediated JAK2/STAT3 signaling pathway. PLoS One. 10:e01234782015. View Article : Google Scholar : PubMed/NCBI

38 

Yan M, Zhang K, Shi Y, Feng L, Lv L and Li B: Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency. Drug Des Devel Ther. 9:5737–5747. 2015.PubMed/NCBI

39 

Zhang K, Zhi D, Huang T, Gong Y, Yan M, Liu C, Wei T, Dong Z, Li B and Yang B: Berberine induces hERG channel deficiency through trafficking inhibition. Cell Physiol Biochem. 34:691–702. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Xia J, Wang H, Li S, Wu Q, Sun L, Huang H and Zeng M: Ion channels or aquaporins as novel molecular targets in gastric cancer. Mol Cancer. 16:542017. View Article : Google Scholar : PubMed/NCBI

41 

Arcangeli A and Becchetti A: Novel perspectives in cancer therapy: Targeting ion channels. Drug Resist Updat 21–22. 11–19. 2015. View Article : Google Scholar

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June 2019
Volume 17 Issue 6

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Copy and paste a formatted citation
APA
Zhi, D., Zhou, K., Yu, D., Fan, X., Zhang, J., Li, X., & Dong, M. (2019). hERG1 is involved in the pathophysiological process and inhibited by berberine in SKOV3 cells. Oncology Letters, 17, 5653-5661. https://doi.org/10.3892/ol.2019.10263
MLA
Zhi, D., Zhou, K., Yu, D., Fan, X., Zhang, J., Li, X., Dong, M."hERG1 is involved in the pathophysiological process and inhibited by berberine in SKOV3 cells". Oncology Letters 17.6 (2019): 5653-5661.
Chicago
Zhi, D., Zhou, K., Yu, D., Fan, X., Zhang, J., Li, X., Dong, M."hERG1 is involved in the pathophysiological process and inhibited by berberine in SKOV3 cells". Oncology Letters 17, no. 6 (2019): 5653-5661. https://doi.org/10.3892/ol.2019.10263