Inhibition of γ‑secretase activity synergistically enhances tumour necrosis factor‑related apoptosis‑inducing ligand induced apoptosis in T‑cell acute lymphoblastic leukemia cells via upregulation of death receptor 5

Greene,Lisa M.; Nathwani,Seema M.; Zisterer,Daniela M.

doi:10.3892/ol.2016.5011

October-2016 Volume 12 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

October-2016 Volume 12 Issue 4

Full Size Image

Article

Inhibition of γ‑secretase activity synergistically enhances tumour necrosis factor‑related apoptosis‑inducing ligand induced apoptosis in T‑cell acute lymphoblastic leukemia cells via upregulation of death receptor 5

Authors:
- Lisa M. Greene
- Seema M. Nathwani
- Daniela M. Zisterer
View Affiliations / Copyright

Affiliations: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland
Pages: 2900-2905
|
Published online on: August 16, 2016

https://doi.org/10.3892/ol.2016.5011
Expand metrics +

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematopoietic malignancy prone to relapse and drug resistance. Half of all T‑ALL patients exhibit mutations in Notch1, which leads to aberrant Notch1 associated signaling cascades. Notch1 activation is mediated by the γ‑secretase cleavage of the Notch1 receptor into the active intracellular domain of Notch1 (NCID). Clinical trials of γ‑secretase small molecule inhibitors (GSIs) as single agents for the treatment of T‑ALL have been unsuccessful. The present study demonstrated, using immunofluorescence and western blotting, that blocking γ‑secretase activity in T‑ALL cells with N‑[(3,5‑difluorophenyl) acetyl]‑L‑alanyl‑2‑phenyl] glycine‑1,1‑dimethylethyl ester (DAPT) downregulated NCID and upregulated the tumour necrosis factor‑related apoptosis‑inducing ligand (TRAIL) death receptor 5 (DR5). Upregulation of DR5 restored the sensitivity of T‑ALL cells to TRAIL. Combination index revealed that the combined treatment of DAPT and TRAIL synergistically enhanced apoptosis compared with treatment with either drug alone. TRAIL combined with the clinically evaluated γ‑secretase inhibitor 3‑[(1r, 4s)‑4‑(4‑chlorophenylsulfonyl)‑4‑(2, 5‑difluorophenyl) cyclohexyl] propanoic acid (MK‑0752) also significantly enhanced TRAIL‑induced cell death compared with either drug alone. DAPT/TRAIL apoptotic synergy was dependent on the extrinsic apoptotic pathway and was associated with a decrease in BH3 interacting‑domain death agonist and x‑linked inhibitor of apoptosis. In conclusion, γ‑secretase inhibition represents a potential therapeutic strategy to overcome TRAIL resistance for the treatment of T‑ALL.

View Figures

View References

1	Ferrando AA: The role of NOTCH1 signaling in T-ALL. Hematology Am Soc Hematol Educ Program. 353–361. 2009.PubMed/NCBI
2	Chiaretti S and Foà R: T-cell acute lymphoblastic leukemia. Haematologica. 94:160–162. 2009. View Article : Google Scholar : PubMed/NCBI
3	Weng AP, Ferrando AA, Lee W, Morris JP IV, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Looks AT and Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 306:269–271. 2004. View Article : Google Scholar : PubMed/NCBI
4	Haydu JE, De Keersmaecker K, Duff MK, Paietta E, Racevskis J, Wiernik PH, Rowe JM and Ferrando A: An activating intragenic deletion in NOTCH1 in human T-ALL. Blood. 119:5211–5214. 2012. View Article : Google Scholar : PubMed/NCBI
5	Groth C and Fortini ME: Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Semin Cell Dev Biol. 23:465–472. 2012. View Article : Google Scholar : PubMed/NCBI
6	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
7	Bray SJ: Notch signalling: A simple pathway becomes complex. Nat Rev Mol Cell Biol. 7:678–689. 2006. View Article : Google Scholar : PubMed/NCBI
8	Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, et al: Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology. 66:602–604. 2006. View Article : Google Scholar : PubMed/NCBI
9	Deangelo DJ, Stone RM, Silverman LB, Stock W, Attar EC, Fearen I, Dallob A, Matthews C, Stone J, Freedman SJ and Aster J: A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol (ASCO Annual Meeting Proceedings). 24:65852006.
10	Kolb EA, Gorlick R, Keir ST, Maris JM, Lock R, Carol H, Kurmasheva RT, Reynolds CP, Kang MH, Wu J, et al: Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling. Pediatr Blood Cancer. 58:815–818. 2012. View Article : Google Scholar : PubMed/NCBI
11	Messersmith WA, Shapiro GI, Cleary JM, Jimeno A, Dasari A, Huang B, Shaik MN, Cesari R, Zheng X, Reynolds JM, et al: A Phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014. Clin Cancer Res. 21:60–67. 2015. View Article : Google Scholar : PubMed/NCBI
12	Litzow MR and Ferrando AA: How I treat T-cell acute lymphoblastic leukemia in adults. Blood. 126:833–841. 2015. View Article : Google Scholar : PubMed/NCBI
13	Amarante-Mendes GP and Griffith TS: Therapeutic applications of TRAIL receptor agonists in cancer and beyond. Pharmacol Ther. 155:117–131. 2015. View Article : Google Scholar : PubMed/NCBI
14	Hellwig CT and Rehm M: TRAIL signaling and synergy mechanisms used in TRAIL-based combination therapies. Mol Cancer Ther. 11:3–13. 2012. View Article : Google Scholar : PubMed/NCBI
15	Akahane K, Inukai T, Zhang X, Hirose K, Kuroda I, Goi K, Honna H, Kagami K, Nakazawa S, Endo K, et al: Resistance of T-cell acute lymphoblastic leukemia to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis. Exp Hematol. 38:885–895. 2010. View Article : Google Scholar : PubMed/NCBI
16	Bijnsdorp IV, Giovannetti E and Peters GJ: Analysis of drug interactions. Methods Mol Biol. 731:421–434. 2011. View Article : Google Scholar : PubMed/NCBI
17	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
18	Van Vlierberghe P and Ferrando A: The molecular basis of T cell acute lymphoplastic leukemia. J Clin Invest. 122:3398–3406. 2012. View Article : Google Scholar : PubMed/NCBI
19	Olsauskas-Kuprys R, Zlobin A and Osipo C: Gamma secretase inhibitors of Notch signaling. Onco Targets Ther. 6:943–955. 2013.PubMed/NCBI
20	Diaz-Padilla I, Wilson MK, Clarke BA, Hirte HW, Welch SA, Mackay HJ, Biagi JJ, Reedijk M, Weberpals JI, Fleming GF, et al: A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia. Gynecol Oncol. 137:216–222. 2015. View Article : Google Scholar : PubMed/NCBI
21	Lee SM, Moon J, Redman BG, Chidiac T, Flaherty LE, Zha Y, Othus M, Ribas A, Sondak VK, Gajewski TF and Margolin KA: Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. Cancer. 121:432–440. 2015. View Article : Google Scholar : PubMed/NCBI
22	LoConte NK, Razak AR, Ivy P, Tevaarwerk A, Leverence R, Kolesar J, Siu L, Lubner SJ, Mulkerin DL, Schelman WR, et al: A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors. Invest New Drugs. 33:169–176. 2015. View Article : Google Scholar : PubMed/NCBI
23	Richter S, Bedard PL, Chen EX, Clarke BA, Tran B, Hotte SJ, Stathis A, Hirte HW, Razak AR, Reedijk M, et al: A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575). Invest New Drugs. 32:243–249. 2014. View Article : Google Scholar : PubMed/NCBI
24	Sahebjam S, Bedard PL, Castonguay V, Chen Z, Reedijk M, Liu G, Cohen B, Zhang WJ, Clarke B, Zhang T, et al: A phase I study of the combination of RO4929097 and cediranib in patients with advanced solid tumours. Br J Cancer. 109:943–949. 2013. View Article : Google Scholar : PubMed/NCBI
25	Diaz-Padilla I, Hirte H, Oza AM, Clarke BA, Cohen B, Reedjik M, Zhang T, Kamel-Reid S, Ivy SP, Hotte SJ, et al: A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest New Drugs. 31:1182–1191. 2013. View Article : Google Scholar : PubMed/NCBI
26	Portanova P, Notaro A, Pellerito O, Sabella S, Giuliano M and Calvaruso G: Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells. Int J Oncol. 43:121–130. 2013.PubMed/NCBI
27	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
28	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 hepatocellular 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 : PubMed/NCBI
29	Naik S, MacFarlane M and Sarin A: Notch4 signaling confers susceptibility to TRAIL-induced apoptosis in breast cancer cells. J Cell Biochem. 116:1371–1380. 2015. View Article : Google Scholar : PubMed/NCBI
30	Li H, Zhu H, Xu CJ and Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 94:491–501. 1998. View Article : Google Scholar : PubMed/NCBI
31	Schug ZT, Gonzalvez F, Houtkooper RH, Vaz FM and Gottlieb E: BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ. 18:538–548. 2011. View Article : Google Scholar : PubMed/NCBI
32	Li S, Zhao Y, He X, Kim TH, Kuharsky DK, Rabinowich H, Chen J, Du C and Yin XM: Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J Biol Chem. 277:26912–26920. 2002. View Article : Google Scholar : PubMed/NCBI
33	Broaddus VC, Dansen TB, Abayasiriwardana KS, Wilson SM, Finch AJ, Swigart LB, Hunt AE and Evan GI: Bid mediates apoptotic synergy between tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and DNA damage. J Biol Chem. 280:12486–12493. 2005. View Article : Google Scholar : PubMed/NCBI
34	Orzechowska EJ, Kozlowska E, Czubaty A, Kozlowski P, Staron K and Trzcinska-Danielewicz J: Controlled delivery of BID protein fused with TAT peptide sensitizes cancer cells to apoptosis. BMC Cancer. 14:7712014. View Article : Google Scholar : PubMed/NCBI
35	Wilkinson JC, Cepero E, Boise LH and Duckett CS: Upstream regulatory role for XIAP in receptor-mediated apoptosis. Mol Cell Biol. 24:7003–7014. 2004. View Article : Google Scholar : PubMed/NCBI
36	Zhang XD, Zhang XY, Gray CP, Nguyen T and Hersey P: Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria. Cancer Res. 61:7339–7348. 2001.PubMed/NCBI
37	Rao SS, O'Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, et al: Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res. 69:3060–3068. 2009. View Article : Google Scholar : PubMed/NCBI