Doxorubicin activates the Notch signaling pathway in osteosarcoma

Mei,Hongjun; Yu,Ling; Ji,Peng; Yang,Jian; Fang,Shuo; Guo,Weichun; Liu,Yang; Chen,Xuanyin

doi:10.3892/ol.2015.3135

Doxorubicin activates the Notch signaling pathway in osteosarcoma

Authors:
- Hongjun Mei
- Ling Yu
- Peng Ji
- Jian Yang
- Shuo Fang
- Weichun Guo
- Yang Liu
- Xuanyin Chen
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Affiliations: Department of Orthopaedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Orthopaedics, Fifth Hospital of Wuhan, Hubei 430050, P.R. China, Department of Orthopaedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: April 21, 2015 https://doi.org/10.3892/ol.2015.3135
Pages: 2905-2909

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Abstract

Notch signaling is critical in various biological processes, including cell proliferation, differentiation and apoptosis. Furthermore, accumulating evidence indicated that aberrant Notch signaling has a tumor‑promoting function in osteosarcoma. However, the effect of the conventional chemotherapeutic agent, doxorubicin, on Notch signaling remains unclear. In the present study, osteosarcoma cells were treated with various concentrations of doxorubicin and the effect on Notch signaling was analyzed. A cytostatic dose of doxorubicin (<0.5 µM) was identified to significantly activate the Notch signaling pathway in a dose‑dependent manner (P<0.01), as demonstrated by the elevated expression levels of Notch target genes. However, a toxic dose of doxorubicin (≥0.5 µM) significantly inhibited the Notch signaling pathway (P<0.01). These results indicated a significant correlation between doxorubicin administration and the Notch signaling pathway. Therefore, the present study supports further investigation into Notch and osteosarcoma chemoresistance.

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1	Jaffe N: Osteosarcoma: review of the past, impact on the future. The American experience. Cancer Treat Res. 152:239–262. 2009.PubMed/NCBI
2	Hansen AR, Hughes BG, Paul S, et al: Single institution retrospective review of perioperative chemotherapy in adult and adolescent patients with operable osteosarcoma. Asia Pac J Clin Oncol. Feb 20–2014.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
3	Haddox CL, Han G, Anijar L, et al: Osteosarcoma in pediatric patients and young adults: a single institution retrospective review of presentation, therapy and outcome. Sarcoma. 2014:4025092014. View Article : Google Scholar : PubMed/NCBI
4	Gelderblom H, Jinks RC, Sydes M, et al: European Osteosarcoma Intergroup: Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer. 47:895–902. 2011. View Article : Google Scholar : PubMed/NCBI
5	Bacci G, Briccoli A, Longhi A, et al: Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol. 44:748–755. 2005. View Article : Google Scholar : PubMed/NCBI
6	He H, Ni J and Huang J: Molecular mechanisms of chemoresistance in osteosarcoma (Review). Oncol Lett. 7:1352–1362. 2014.PubMed/NCBI
7	Martins-Neves SR, Lopes AO, do Carmo A, et al: Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line. BMC Cancer. 12:1392012. View Article : Google Scholar : PubMed/NCBI
8	Gibbs CP Jr, Levings PP and Ghivizzani SC: Evidence for the osteosarcoma stem cell. Curr Orthop Pract. 22:322–326. 2011. View Article : Google Scholar : PubMed/NCBI
9	Siclari VA and Qin L: Targeting the osteosarcoma cancer stem cell. J Orthop Surg. 5:782010. View Article : Google Scholar
10	Yu L, Liu S, Zhang C, et al: Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity. Oncotarget. 4:2326–2338. 2013.PubMed/NCBI
11	Adhikari AS, Agarwal N, Wood BM, et al: CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res. 70:4602–4612. 2010. View Article : Google Scholar : PubMed/NCBI
12	Guruharsha KG, Kankel MW and Artavanis-Tsakonas S: The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet. 13:654–666. 2012. View Article : Google Scholar : PubMed/NCBI
13	Bianchi S, Dotti MT and Federico A: Physiology and pathology of notch signalling system. J Cell Physiol. 207:300–308. 2006. View Article : Google Scholar : PubMed/NCBI
14	Fortini ME: Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 16:633–647. 2009. View Article : Google Scholar : PubMed/NCBI
15	Davis RL and Turner DL: Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene. 20:8342–8357. 2001. View Article : Google Scholar : PubMed/NCBI
16	Aranguren XL, Agirre X, Beerens M, et al: Unraveling a novel transcription factor code determining the human arterial-specific endothelial cell signature. Blood. 122:3982–3992. 2013. View Article : Google Scholar : PubMed/NCBI
17	Jin HY, Zhang HY, Wang X, Xu J and Ding Y: Expression and clinical significance of Notch signaling genes in colorectal cancer. Tumour Biol. 33:817–824. 2012. View Article : Google Scholar : PubMed/NCBI
18	Ungerbӓck J, Elander N, Grünberg J, Sigvardsson M and Söderkvist P: The Notch-2 gene is regulated by Wnt signaling in cultured colorectal cancer cells. PLoS One. 6:e179572011. View Article : Google Scholar : PubMed/NCBI
19	Mysliwiec P and Boucher MJ: Targeting Notch signaling in pancreatic cancer patients - rationale for new therapy. Adv Med Sci. 54:136–142. 2009. View Article : Google Scholar : PubMed/NCBI
20	Avila JL and Kissil JL: Notch signaling in pancreatic cancer: oncogene or tumor suppressor? Trends Mol Med. 19:320–327. 2013. View Article : Google Scholar : PubMed/NCBI
21	Maliekal TT, Bajaj J, Giri V, Subramanyam D and Krishna S: The role of Notch signaling in human cervical cancer: implications for solid tumors. Oncogene. 27:5110–5114. 2008. View Article : Google Scholar : PubMed/NCBI
22	McManus MM, Weiss KR and Hughes DP: Understanding the role of notch in osteosarcoma. Adv Exp Med Biol. 804:67–92. 2014.PubMed/NCBI
23	Mu X, Isaac C, Greco N, Huard J and Weiss K: Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells. Front Oncol. 3:1432013. View Article : Google Scholar : PubMed/NCBI
24	Ma Y, Ren Y, Han EQ, et al: Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun. 431:274–279. 2013. View Article : Google Scholar : PubMed/NCBI
25	Hughes DP: How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treat Res. 152:479–496. 2009.PubMed/NCBI
26	Tanaka M, Setoguchi T, Hirotsu M, et al: Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer. 100:1957–1965. 2009. View Article : Google Scholar : PubMed/NCBI
27	Yu L, Liu S, Guo W, et al: hTERT promoter activity identifies osteosarcoma cells with increased EMT characteristics. Oncol Lett. 7:239–244. 2014.PubMed/NCBI
28	Thorn CF, Oshiro C, Marsh S, et al: Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 21:440–446. 2011. View Article : Google Scholar : PubMed/NCBI
29	Liu YP, Yang CJ, Huang MS, et al: Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling. Cancer Res. 73:406–416. 2013. View Article : Google Scholar : PubMed/NCBI
30	Liu J and Mao Z, Huang J, Xie S, Liu T and Mao Z: Blocking the NOTCH pathway can inhibit the growth of CD133-positive A549 cells and sensitize to chemotherapy. Biochem Biophys Res Commun. 444:670–675. 2014. View Article : Google Scholar : PubMed/NCBI
31	Wang M, Ma X, Wang J, Wang L and Wang Y: Pretreatment with the γ-secretase inhibitor DAPT sensitizes drug-resistant ovarian cancer cells to cisplatin by downregulation of Notch signaling. Int J Oncol. 44:1401–1409. 2014.PubMed/NCBI
32	Zhou JX, Han JB, Chen SM, et al: γ-secretase inhibition combined with cisplatin enhances apoptosis of nasopharyngeal carcinoma cells. Exp Ther Med. 3:357–361. 2012.PubMed/NCBI
33	Zang S, Chen F, Dai J, et al: RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer. Oncol Rep. 23:893–899. 2010.PubMed/NCBI
34	Nefedova Y, Sullivan DM, Bolick SC, Dalton WS and Gabrilovich DI: Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 111:2220–2229. 2008. View Article : Google Scholar : PubMed/NCBI
35	Zhang ZP, Sun YL, Fu L, Gu F, Zhang L and Hao XS: Correlation of Notch1 expression and activation to cisplatin-sensitivity of head and neck squamous cell carcinoma. Ai Zheng. 28:100–103. 2009.PubMed/NCBI