Open AccessIL13Rα2‑ and EGFR‑targeted pseudomonas exotoxin potentiates the TRAIL‑mediated death of GBM cells
Author(s) -
Nihal Karakaş,
Daniel W. Stuckey,
Esther Revai Lechtich,
Khalid Shah
Publication year - 2021
Publication title -
international journal of molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.048
H-Index - 90
eISSN - 1791-244X
pISSN - 1107-3756
DOI - 10.3892/ijmm.2021.4978
Subject(s) - pseudomonas exotoxin , xiap , cancer research , apoptosis , epidermal growth factor receptor , tumor necrosis factor alpha , biology , egfr inhibitors , caspase , programmed cell death , receptor , immunology , cytotoxicity , biochemistry , in vitro
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.