Functional redundancy of the Notch pathway in ovarian cancer cell lines

Silva,Fernanda; Félix,Ana; Serpa,Jacinta

doi:10.3892/ol.2016.4959

Functional redundancy of the Notch pathway in ovarian cancer cell lines

Authors:
- Fernanda Silva
- Ana Félix
- Jacinta Serpa
View Affiliations

Affiliations: Chronic Diseases Research Center (CEDOC‑FCM‑UNL), NOVA Medical School, NOVA University of Lisbon, Lisbon 1169‑056, Portugal
Published online on: August 5, 2016 https://doi.org/10.3892/ol.2016.4959
Pages: 2686-2691

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy, despite advances in treatment. The most common histological type, high‑grade ovarian serous carcinoma (OSC) is usually diagnosed at an advanced stage, and although these types of tumors frequently respond to surgery and platinum‑based chemotherapy, they usually recur. Ovarian clear cell carcinoma (OCCC) is an unusual histological type, which is known to be intrinsically chemoresistant and is associated with poor prognosis in advanced stages. In recent years, genetic alterations and epigenetic modulation of signaling pathways have been reported in OSC and OCCC, including the overexpression of Notch pathway elements and histone deacetylases. Histone deacetylase inhibitors (HDACis), including vorinostat (suberoylanilide hydroxamic acid), alter the transcription of genes involved in cell growth, survival and apoptosis, and have become an attractive therapeutic approach. However, no previous work has addressed the effect of HDACis, and in particular vorinostat, on Notch signaling in ovarian cancer. Therefore, the present study aimed to investigate the modulation of the Notch pathway by vorinostat in ovarian cancer. Using immunofluorescence and quantitative polymerase chain reaction, the present results revealed that vorinostat activated the Notch pathway in OCCC and OSC cell lines, through different Notch ligands. In OCCC, the activation of the Notch pathway appeared to occur through Delta‑like (Dll) ligands 1, 2 and 3, whereas in OSC Dll1 and Jagged 1 and 2 ligands were involved. The activation of the Notch pathway by vorinostat, in OCCC and OSC cell lines, culminated in the increased expression of the same downstream transcription factors, hairy enhancer of split (Hes) 1 and 5, and Hes‑related proteins 1 and 2. In conclusion, vorinostat modulates the expression of several downstream targets of the Notch pathway and independent Notch receptors and ligands that are expressed in OSC and OCCC. This upregulation of the Notch pathway may explain why vorinostat therapy fails in ovarian carcinoma treatment, as shown in certain clinical trials.

View Figures

View References

1	Reinhardt MJ: Gynecologic tumorsPET in Oncology. Dresel S: 170. Springer; Berlin: pp. 141–150. 2008, View Article : Google Scholar
2	Bast RC, Hennessy B and Mills GB: The biology of ovarian cancer: New opportunities for translation. Nat Rev Cancer. 9:415–428. 2009. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
4	Smolle E, Taucher V, Pichler M, Petru E, Lax S and Haybaeck J: Targeting signaling pathways in epithelial ovarian cancer. Int J Mol Sci. 14:9536–9555. 2013. View Article : Google Scholar : PubMed/NCBI
5	Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar : PubMed/NCBI
6	DelCarmen MG, Birrer M and Schorge JO: Clear cell carcinoma of the ovary: A review of the literature. Gynecol Oncol. 126:481–490. 2012. View Article : Google Scholar : PubMed/NCBI
7	Ayhan A, Mao TL, Seckin T, Wu CH, Guan B, Ogawa H, Futagami M, Mizukami H, Yokoyama Y, Kurman RJ and Shih IeM: Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma. Int J Gynecol Cancer. 22:1310–1305. 2012. View Article : Google Scholar : PubMed/NCBI
8	Guan B, Wang TL and Shih IM: ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res. 71:6718–6727. 2011. View Article : Google Scholar : PubMed/NCBI
9	Kotsopoulos IC, Papanikolaou A, Lambropoulos AF, Papazisis KT, Tsolakidis D, Touplikioti P and Tarlatzis BC: Serous ovarian cancer signaling pathways. Int J Gynecol Cancer. 24:410–417. 2014. View Article : Google Scholar : PubMed/NCBI
10	Jin KL, Pak JH, Park JY, Choi WH, Lee JY, Kim JH and Nam JH: Expression profile of histone deacetylases 1, 2 and 3 in ovarian cancer tissues. J Gynecol Oncol. 19:185–190. 2008. View Article : Google Scholar : PubMed/NCBI
11	Ranganathan P, Weaver KL and Capobianco AJ: Notch signalling in solid tumours: A little bit of everything but not all the time. Nat Rev Cancer. 11:338–351. 2011. View Article : Google Scholar : PubMed/NCBI
12	Takebe N, Nguyen D and Yang SX: Targeting notch signaling pathway in cancer: Clinical development advances and challenges. Pharmacol Ther. 141:140–149. 2014. View Article : Google Scholar : PubMed/NCBI
13	Nickoloff BJ, Osborne BA and Miele L: Notch signaling as a therapeutic target in cancer: A new approach to the development of cell fate modifying agents. Oncogene. 22:6598–6608. 2003. View Article : Google Scholar : PubMed/NCBI
14	Aster JC and Blacklow SC: Targeting the Notch pathway: Twists and turns on the road to rational therapeutics. J Clin Oncol. 30:2418–2420. 2012. View Article : Google Scholar : PubMed/NCBI
15	Li JL and Harris AL: Notch signaling from tumor cells: A new mechanism of angiogenesis. Cancer Cell. 8:1–3. 2005. View Article : Google Scholar : PubMed/NCBI
16	Dufraine J, Funahashi Y and Kitajewski J: Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 27:5132–5137. 2008. View Article : Google Scholar : PubMed/NCBI
17	Fleming RJ, Purcell K and Artavanis-Tsakonas S: The NOTCH receptor and its ligands. Trends Cell Biol. 7:437–441. 1997. View Article : Google Scholar : PubMed/NCBI
18	Lendahl U: A growing family of Notch ligands. Bioessays. 20:103–107. 1998. View Article : Google Scholar : PubMed/NCBI
19	Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, IshHorowitz D and Artavanis-Tsakonas S: Human ligands of the Notch receptor. Am J Pathol. 154:785–794. 1999. View Article : Google Scholar : PubMed/NCBI
20	Yamaguchi E, Chiba S, Kumano K, Kunisato A, Takahashi T, Takahashi T and Hirai H: Expression of Notch ligands, Jagged1, 2 and Delta1 in antigen presenting cells in mice. Immunol Lett. 81:59–64. 2002. View Article : Google Scholar : PubMed/NCBI
21	Kao HY, Ordentlich P, KoyanoNakagawa N, Tang Z, Downes M, Kintner CR, Evans RM and Kadesch T: A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. 12:2269–2277. 1998. View Article : Google Scholar : PubMed/NCBI
22	Ronchini C and Capobianco AJ: Induction of cyclin D1 transcription and CDK2 activity by Notch (ic): Implication for cell cycle disruption in transformation by Notch (ic). Mol Cell Biol. 21:5925–5934. 2001. View Article : Google Scholar : PubMed/NCBI
23	Weng AP, Millholland JM, YashiroOhtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, et al: c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20:2096–2109. 2006. View Article : Google Scholar : PubMed/NCBI
24	Hirose H, Ishii H, Mimori K, Ohta D, Ohkuma M, Tsujii H, Saito T, Sekimoto M, Doki Y and Mori M: Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors. Oncol Rep. 23:35–43. 2010.PubMed/NCBI
25	Takai N and Narahara H: Histone deacetylase inhibitor therapy in epithelial ovarian cancer. J Oncol. 2010:4584312010. View Article : Google Scholar : PubMed/NCBI
26	Bolden JE, Peart MJ and Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 5:769–784. 2006. View Article : Google Scholar : PubMed/NCBI
27	Richon VM: Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer. 95(Suppl 1): S2–S6. 2006. View Article : Google Scholar
28	Cooper AL, Greenberg VL, Lancaster PS, Van Nagell JR Jr, Zimmer SG and Modesitt SC: In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer. Gynecol Oncol. 104:596–601. 2007. View Article : Google Scholar : PubMed/NCBI
29	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
30	Bolós V, Grego-Bessa J and de la Pompa JL: Notch signaling in development and cancer. Endocr Rev. 28:339–363. 2007. View Article : Google Scholar : PubMed/NCBI
31	McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW, Chen YS, Chin KT, Partridge JC, Poole BB, Cheng KH, et al: Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci USA. 109:E2939–E2948. 2012. View Article : Google Scholar : PubMed/NCBI
32	Rose SL, Kunnimalaiyaan M, Drenzek J and Seiler N: Notch 1 signaling is active in ovarian cancer. Gynecol Oncol. 117:130–133. 2010. View Article : Google Scholar : PubMed/NCBI
33	Hopfer O, Zwahlen D, Fey MF and Aebi S: The Notch pathway in ovarian carcinomas and adenomas. Br J Cancer. 93:709–718. 2005. View Article : Google Scholar : PubMed/NCBI
34	Capaccione KM and Pine SR: The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 34:1420–1430. 2013. View Article : Google Scholar : PubMed/NCBI
35	Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM and Wang TL: Notch3 gene amplification in ovarian cancer. Cancer Res. 66:6312–6387. 2006. View Article : Google Scholar : PubMed/NCBI
36	Park JT, Chen X, Tropè CG, Davidson B, Shih IM and Wang TL: Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin. Am J Pathol. 177:1087–1094. 2010. View Article : Google Scholar : PubMed/NCBI
37	Tan DSP, Miller RE and Kaye SB: New perspectives on molecular targeted therapy in ovarian clear cell carcinoma. Br J Cancer. 108:1553–1559. 2013. View Article : Google Scholar : PubMed/NCBI
38	Jung SG, Kwon YD, Song JA, Back MJ, Lee SY, Lee C, Hwang YY and An HJ: Prognostic significance of Notch 3 gene expression in ovarian serous carcinoma. Cancer Sci. 101:1977–1983. 2010. View Article : Google Scholar : PubMed/NCBI
39	Iso T, Kedes L and Hamamori Y: HES and HERP families: Multiple effectors of the Notch signaling pathway. J Cell Physiol. 194:237–255. 2003. View Article : Google Scholar : PubMed/NCBI