IL13Rα2‑ and EGFR‑targeted pseudomonas exotoxin potentiates the TRAIL‑mediated death of GBM cells

Karakaş,Nihal; Stuckey,Daniel; Revai‑Lechtich,Esther; Shah,Khalid

doi:10.3892/ijmm.2021.4978

IL13Rα2‑ and EGFR‑targeted pseudomonas exotoxin potentiates the TRAIL‑mediated death of GBM cells

Authors:
- Nihal Karakaş
- Daniel Stuckey
- Esther Revai‑Lechtich
- Khalid Shah
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Affiliations: Center for Stem Cell Therapeutics and Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
Published online on: June 3, 2021 https://doi.org/10.3892/ijmm.2021.4978
Article Number: 145

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Abstract

Glioblastomas (GBMs) are refractory to current treatments and novel therapeutic approaches need to be explored. Pro‑apoptotic tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) is tumor‑specific and has been shown to induce apoptosis and subsequently kill GBM cells. However, approximately 50% of GBM cells are resistant to TRAIL and a combination of TRAIL with other therapeutics is necessary to induce mechanism‑based cell death in TRAIL‑resistant GBMs. The present study examined the ability of the tumor cell surface receptor, interleukin (IL)‑13 receptor α2 (IL13Rα2)‑ and epidermal growth factor receptor (EGFR)‑targeted pseudomonas exotoxin (PE) to sensitize TRAIL‑resistant GBM cells and assessed the dual effects of interleukin 13‑PE (IL13‑PE) or EGFR nanobody‑PE (ENb‑PE) and TRAIL for the treatment of a broad range of brain tumors with a distinct TRAIL therapeutic response. Receptor targeted toxins upregulated TRAIL death receptors (DR4 and DR5) and suppressed the expression of anti‑apoptotic FLICE‑inhibitory protein (FLIP) and X‑linked inhibitor of apoptosis protein (XIAP). This also led to the induction of the cleavage of caspase‑8 and caspase‑9 and resulted in the sensitization of highly resistant established GBM and patient‑derived GBM stem cell (GSC) lines to TRAIL‑mediated apoptosis. These findings provide a mechanism‑based strategy that may provide options for the cell‑mediated delivery of bi‑functional therapeutics to target a wide spectrum of TRAIL‑resistant GBMs.

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1	Su Z, Zang T, Liu ML, Wang LL, Niu W and Zhang CL: Reprogramming the fate of human glioma cells to impede brain tumor development. Cell Death Dis. 5:e14632014. View Article : Google Scholar : PubMed/NCBI
2	Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI
3	Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 352:997–1003. 2005. View Article : Google Scholar : PubMed/NCBI
4	Martinez R, Rohde V and Schackert G: Different molecular patterns in glioblastoma multiforme subtypes upon recurrence. J Neurooncol. 96:321–329. 2010. View Article : Google Scholar :
5	Bastien JI, McNeill KA and Fine HA: Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer. 121:502–516. 2015. View Article : Google Scholar
6	Karsy M, Gelbman M, Shah P, Balumbu O, Moy F and Arslan E: Established and emerging variants of glioblastoma multiforme: Review of morphological and molecular features. Folia Neuropathol. 50:301–321. 2012. View Article : Google Scholar
7	Cuddapah VA, Robel S, Watkins S and Sontheimer H: A neurocentric perspective on glioma invasion. Nat Rev Neurosci. 15:455–465. 2014. View Article : Google Scholar : PubMed/NCBI
8	Carlsson SK, Brothers SP and Wahlestedt C: Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. 6:1359–1370. 2014. View Article : Google Scholar : PubMed/NCBI
9	Fialho AM, Salunkhe P, Manna S, Mahali S and Chakrabarty AM: Glioblastoma multiforme: Novel therapeutic approaches. ISRN Neurol. 2012:6423452012. View Article : Google Scholar : PubMed/NCBI
10	Kim K, Fisher MJ, Xu SQ and el-Deiry WS: Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res. 6:335–346. 2000.PubMed/NCBI
11	Suliman A, Lam A, Datta R and Srivastava RK: Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene. 20:2122–2133. 2001. View Article : Google Scholar : PubMed/NCBI
12	Stuckey DW and Shah K: TRAIL on trial: Preclinical advances in cancer therapy. Trends Mol Med. 19:685–694. 2013. View Article : Google Scholar : PubMed/NCBI
13	Bagci-Onder T, Agarwal A, Flusberg D, Wanningen S, Sorger P and Shah K: Real-time imaging of the dynamics of death receptors and therapeutics that overcome TRAIL resistance in tumors. Oncogene. 32:2818–2827. 2013. View Article : Google Scholar :
14	Deng Y, Lin Y and Wu X: TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev. 16:33–45. 2002. View Article : Google Scholar : PubMed/NCBI
15	Kauer TM, Figueiredo JL, Hingtgen S and Shah K: Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas. Nat Neurosci. 15:197–204. 2011. View Article : Google Scholar : PubMed/NCBI
16	Bagci-Onder T, Wakimoto H, Anderegg M, Cameron C and Shah K: A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models. Cancer Res. 71:154–163. 2011. View Article : Google Scholar
17	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
18	Du W, Uslar L, Sevala S and Shah K: Targeting c-Met receptor overcomes TRAIL-resistance in brain tumors. PLoS One. 9:e954902014. View Article : Google Scholar : PubMed/NCBI
19	Finlay D, Richardson RD, Landberg LK, Howes AL and Vuori K: Novel HTS strategy identifies TRAIL-sensitizing compounds acting specifically through the caspase-8 apoptotic axis. PLoS One. 5:e133752010. View Article : Google Scholar : PubMed/NCBI
20	Zhou X, Qiu J, Wang Z, Huang N, Li X, Li Q, Zhang Y, Zhao C, Luo C, Zhang N, et al: In vitro and in vivo anti-tumor activities of anti-EGFR single-chain variable fragment fused with recombinant gelonin toxin. J Cancer Res Clin Oncol. 138:1081–1090. 2012. View Article : Google Scholar : PubMed/NCBI
21	Horita H, Thorburn J, Frankel AE and Thorburn A: EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins. J Neurooncol. 95:175–184. 2009. View Article : Google Scholar : PubMed/NCBI
22	Stuckey DW, Hingtgen SD, Karakas N, Rich BE and Shah K: Engineering toxin-resistant therapeutic stem cells to treat brain tumors. Stem Cells. 33:589–600. 2015. View Article : Google Scholar :
23	Thaci B, Brown CE, Binello E, Werbaneth K, Sampath P and Sengupta S: Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy. Neuro Oncol. 16:1304–1312. 2014. View Article : Google Scholar : PubMed/NCBI
24	Heimberger AB, Suki D, Yang D, Shi W and Aldape K: The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med. 3:382005. View Article : Google Scholar : PubMed/NCBI
25	Terabe M, Park JM and Berzofsky JA: Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother. 53:79–85. 2004. View Article : Google Scholar
26	Maletinska L, Blakely EA, Bjornstad KA, Deen DF, Knoff LJ and Forte TM: Human glioblastoma cell lines: Levels of low-density lipoprotein receptor and low-density lipoprotein receptor-related protein. Cancer Res. 60:2300–2303. 2000.PubMed/NCBI
27	Wolf P and Elsasser-Beile U: Pseudomonas exotoxin A: From virulence factor to anti-cancer agent. Int J Med Microbiol. 299:161–176. 2009. View Article : Google Scholar
28	Weldon JE and Pastan I: A guide to taming a toxin-recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. FEBS J. 278:4683–4700. 2011. View Article : Google Scholar : PubMed/NCBI
29	Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, et al: Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. 12:871–881. 2010. View Article : Google Scholar : PubMed/NCBI
30	Auffinger B, Thaci B, Nigam P, Rincon E, Cheng Y and Lesniak MS: New therapeutic approaches for malignant glioma: In search of the Rosetta stone. F1000 Med Rep. 4:182012. View Article : Google Scholar : PubMed/NCBI
31	van de Water JA, Bagci-Onder T, Agarwal AS, Wakimoto H, Roovers RC, Zhu Y, Kasmieh R, Bhere D, Van Bergen en Henegouwen PM and Shah K: Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects. Proc Natl Acad Sci USA. 109:16642–16647. 2012. View Article : Google Scholar : PubMed/NCBI
32	Shah K, Hingtgen S, Kasmieh R, Figueiredo JL, Garcia-Garcia E, Martinez-Serrano A, Breakefield X and Weissleder R: Bimodal viral vectors and in vivo imaging reveal the fate of human neural stem cells in experimental glioma model. J Neurosci. 28:4406–4413. 2008. View Article : Google Scholar : PubMed/NCBI
33	Shah K, Tang Y, Breakefield X and Weissleder R: Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo. Oncogene. 22:6865–6872. 2003. View Article : Google Scholar : PubMed/NCBI
34	Wakimoto H, Kesari S, Farrell CJ, Curry WT Jr, Zaupa C, Aghi M, Kuroda T, Stemmer-Rachamimov A, Shah K, Liu TC, et al: Human glioblastoma-derived cancer stem cells: Establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res. 69:3472–3481. 2009. View Article : Google Scholar : PubMed/NCBI
35	Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
36	Gimple RC, Bhargava S, Dixit D and Rich JN: Glioblastoma stem cells: Lessons from the tumor hierarchy in a lethal cancer. Genes Dev. 33:591–609. 2019. View Article : Google Scholar : PubMed/NCBI
37	Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL and Yu JS: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 5:672006. View Article : Google Scholar : PubMed/NCBI
38	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
39	Reinshagen C, Bhere D, Choi SH, Hutten S, Nesterenko I, Wakimoto H, Le Roux E, Rizvi A, Du W, Minicucci C and Shah K: CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors. Sci Trans Med. 10:eaao32402018. View Article : Google Scholar
40	Dilshara MG, Jayasooriya RGPT, Molagoda IMN, Jeong JW, Lee S, Park SR, Kim GY and Choi YH: Silibinin sensitizes TRAIL-mediated apoptosis by upregulating DR5 through ROS-induced endoplasmic reticulum stress-Ca(2+)-CaMKII-Sp1 pathway. Oncotarget. 9:10324–10342. 2018. View Article : Google Scholar : PubMed/NCBI