Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells

Portanova,Patrizia; Notaro,Antonietta; Pellerito,Ornella; Sabella,Selenia; Giuliano,Michela; Calvaruso,Giuseppe

doi:10.3892/ijo.2013.1945

Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells

Authors:
- Patrizia Portanova
- Antonietta Notaro
- Ornella Pellerito
- Selenia Sabella
- Michela Giuliano
- Giuseppe Calvaruso
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Affiliations: Dipartimento di Medicina traslazionale, Università del Piemonte Orientale, Novara, Italy, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Palermo, Italy, Laboratory of Cellular and Developmental Genetics, Department of Molecular Biology, Medical Biochemistry and Pathology, University of Laval, Québec, Canada
Published online on: May 17, 2013 https://doi.org/10.3892/ijo.2013.1945
Pages: 121-130

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Abstract

Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by γ-secretase targets genes which participate in cell development, differentiation and tumorigenesis. Notch signaling is constitutively activated in various cancers, including breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with γ-secretase inhibitors (GSIs) is considered a promising strategy for cancer treatment. We report that the γ-secretase inhibitor-I (GSI-I) sensitizes human breast cancer cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231 breast cancer cells compared with ER-positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5 TRAIL receptors. This effect seemed to be related to the activation of the transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (survivin, c-IAP-2, Bcl-xL, BimEL and pAKT) and upregulation of pro-apoptotic factors BimL, BimS and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for breast cancer treatment.

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1.	Dotto GP: Notch tumor suppressor function. Oncogene. 27:5115–5123. 2008. View Article : Google Scholar : PubMed/NCBI
2.	Fortini ME: Notch signaling: the core pathway and its post-translational regulation. Dev Cell. 16:633–647. 2009. View Article : Google Scholar : PubMed/NCBI
3.	Miele L, Miao H and Nickoloff BJ: Notch signaling as a novel cancer therapeutic target. Curr Cancer Drug Targets. 6:313–323. 2006. View Article : Google Scholar : PubMed/NCBI
4.	Zardawi SJ, O’Toole SA, Sutherland RL and Musgrove EA: Dysregulation of Hedgehog, Wnt and Notch signaling pathways in breast cancer. Histol Histopathol. 24:385–398. 2009.PubMed/NCBI
5.	Sonoshita M, Aoki M, Fuwa H, Aoki K, Hosogi H, Sakai Y, Hashida H, Takabayashi A, Sasaki M, Robine S, Itoh K, Yoshioka K, Kakizaki F, Kitamura T, Oshima M and Taketo MM: Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell. 19:125–137. 2011. View Article : Google Scholar : PubMed/NCBI
6.	Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Wojewoda C, Miele L and Sarkar FH: Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem. 112:78–88. 2011. View Article : Google Scholar : PubMed/NCBI
7.	Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ and Powell MB: Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest. 118:3660–3670. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Aster JC, Blacklow SC and Pear WS: Notch signaling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. J Pathol. 223:262–273. 2011. View Article : Google Scholar : PubMed/NCBI
9.	Wang Z, Li Y, Banerjee S and Sarkar FH: Exploitation of the Notch signaling pathway as a novel target for cancer therapy. Anticancer Res. 28:3621–3630. 2008.PubMed/NCBI
10.	Bergmans BA and De Strooper B: Gamma-secretase: from cell biology to therapeutic strategies. Lancet Neurol. 9:215–226. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Panza F, Frisardi V, Imbimbo BP, Capurso C, Logroscino G, Sancarlo D, Seripa D, Vendemiale G, Pilotto A and Solfrizzi V: γ-secretase inhibitors for the treatment of Alzheimer’s disease: the current state. CNS Neurosci Ther. 16:272–284. 2010.
12.	Lin J, Zhang XM, Yang JC, Ye YB and Luo SQ: γ-secretase inhibitor-I enhances radiosensitivity of glioblastoma cell lines by depleting CD133⁺ tumor cells. Arch Med Res. 41:519–529. 2010.
13.	Wang S and El-Deiry WS: TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 22:8628–8633. 2003. View Article : Google Scholar : PubMed/NCBI
14.	Zhang XD, Nguyen T, Thomas WD, Sanders JE and Hersey P: Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types. FEBS Lett. 482:193–199. 2000. View Article : Google Scholar : PubMed/NCBI
15.	Zhang L and Fang B: Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12:228–237. 2005. View Article : Google Scholar : PubMed/NCBI
16.	Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ and Ashkenazi A: Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity. 12:611–620. 2000. View Article : Google Scholar : PubMed/NCBI
17.	Van Geelen CM, Pennarun B, Le PT, De Vries EG and De Jong S: Modulation of TRAIL resistance in colon carcinoma cells: different contributions of DR4 and DR5. BMC Cancer. 11:39–51. 2011.PubMed/NCBI
18.	Pellerito O, Calvaruso G, Portanova P, De Blasio A, Santulli A, Vento R, Tesoriere G and Giuliano M: The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating p8/CCAAT/enhancer binding protein homologous protein (CHOP)/death receptor 5 (DR5) axis. Mol Pharmacol. 77:854–863. 2010.
19.	Kahana S, Finniss S, Cazacu S, Xiang C, Lee HK, Brodie S, Goldstein RS, Roitman V, Slavin S, Mikkelsen T and Brodie C: Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent down-regulation of AKT and XIAP expressions. Cell Signal. 23:1348–1357. 2011.PubMed/NCBI
20.	Lauricella M, Ciraolo A, Carlisi D, Vento R and Tesoriere G: SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells. Biochimie. 94:287–299. 2012. View Article : Google Scholar : PubMed/NCBI
21.	Barten DM, Meredith JE Jr, Zaczek R, Houston JG and Albright CF: Gamma-secretase inhibitors for Alzheimer’s disease: balancing efficacy and toxicity. Drugs RD. 7:87–97. 2006.
22.	Okuhashi Y, Itoh M, Nara N and Tohda S: Effects of combination of notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells. Anticancer Res. 31:893–896. 2011.PubMed/NCBI
23.	Chen F, Pisklakova A, Li M, Baz R, Sullivan DM and Nefedova Y: Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma. Cell Oncol (Dordr). 34:545–551. 2011. View Article : Google Scholar : PubMed/NCBI
24.	Giuliano M, Pellerito O, Portanova P, Calvaruso G, Santulli A, De Blasio A, Vento R and Tesoriere G: Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma. Biochimie. 91:457–465. 2009. View Article : Google Scholar : PubMed/NCBI
25.	Calvaruso G, Giuliano M, Portanova P, Pellerito O, Vento R and Tesoriere G: Hsp72 controls bortezomib-induced HepG2 cell death via interaction with pro-apoptotic factors. Oncol Rep. 18:447–450. 2007.PubMed/NCBI
26.	Rizzo P, Miao H, D’Souza G, Osipo C, Song LL, Yun J, Zhao H, Mascarenhas J, Wyatt D, Antico G, Hao L, Yao K, Rajan P, Hicks C, Siziopikou K, Selvaggi S, Bashir A, Bhandari D, Marchese A, Lendahl U, Qin JZ, Tonetti DA, Albain K, Nickoloff BJ and Miele L: Cross-talk between Notch and the estrogen receptor in breast cancer suggest novel therapeutic approaches. Cancer Res. 68:5226–5235. 2008. View Article : Google Scholar : PubMed/NCBI
27.	Chou TC and Talalay P: Quantitative analysis of dose effect relationship: the combined effect of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
28.	LeBlanc HN and Ashkenazi A: Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 10:66–75. 2003. View Article : Google Scholar : PubMed/NCBI
29.	Zou W, Liu X, Yue P, Zhou Z, Sporn MB, Lotan R, Khuri FR and Sun SY: c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 64:7570–7578. 2004. View Article : Google Scholar
30.	Day TW, Huang S and Safa AR: c-FLIP knockdown induces ligand-independent DR5-, -FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells. Biochem Pharmacol. 76:1694–1704. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Youle RJ and Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar : PubMed/NCBI
32.	O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S and Huang DC: Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 17:384–395. 1998.
33.	Li F: Role of survivin and its splice variants in tumorigenesis. Br J Cancer. 92:212–216. 2005.PubMed/NCBI
34.	Ryan B, O’Donovan N, Browne B, O’Shea C, Crown J, Hill AD, McDermott E, O’Higgins N and Duffy MJ: Expression of surviving and its splice variants surviving-2B and surviving-Ex3 in breast cancer. Br J Cancer. 92:120–124. 2005. View Article : Google Scholar : PubMed/NCBI
35.	Ghayad SE and Cohen PA: Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov. 5:29–57. 2010. View Article : Google Scholar : PubMed/NCBI
36.	Carnero A: The PKB/AKT pathway in cancer. Curr Pharm Des. 16:34–44. 2010. View Article : Google Scholar : PubMed/NCBI
37.	Tenzer A, Zingg D, Rocha S, Hemmings B, Fabbro D, Glanzmann C, Schubiger PA, Bodis S and Pruschy M: The phosphatidylinositide 3′-kinase/Akt survival pathway is a target for the anticancer and radiosensitizing agent PKC412, an inhibitor of protein kinase C. Cancer Res. 61:8203–8210. 2001.
38.	Chen JQ and Russo J: ERalpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim Biophys Acta. 1796:162–175. 2009.PubMed/NCBI
39.	Borggrefe T and Oswald F: The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. 66:1631–1646. 2009. View Article : Google Scholar : PubMed/NCBI
40.	Chu J, Jeffties S, Norton JE, Capobianco AJ and Bresnick EH: Repression of activator protein-1 mediated transcriptional activation by the Notch-1 intracellular domain. J Biol Chem. 277:7587–7597. 2002. View Article : Google Scholar : PubMed/NCBI
41.	Kim JW, Kim MJ, Kim KJ, Yun HJ, Chae JS, Hwang SG, Chang TS, Park HS, Lee KW, Han PL, Cho SG, Kim TW and Choi EJ: Notch interferes with the scaffold function of JNK-interacting protein 1 to inhibit the JNK signaling pathway. Proc Natl Acad Sci USA. 102:14308–14313. 2005. View Article : Google Scholar : PubMed/NCBI
42.	Han J, Ma I, Hendzel MJ and Allalunis-Turner J: The cytotoxicity of gamma-secretase inhibitor I to breast cancer cells is mediated by proteasome inhibition, not by gamma-secretase inhibition. Breast Cancer Res. 11:R572009. View Article : Google Scholar : PubMed/NCBI
43.	Lee CW, Raskett CM, Prudovsky I and Altieri DC: Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis. Cancer Res. 68:5273–5281. 2008. View Article : Google Scholar : PubMed/NCBI
44.	Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, Yu Y and Cao X: Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepato-cellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem. 284:16183–16190. 2009. View Article : Google Scholar