Suppressing TRAP1 sensitizes glioblastoma multiforme cells to temozolomide

Abstract

Glioma is a common malignant tumor of the central nervous system, accounting for ~50% of intracranial tumors. The current standard therapy for glioma is surgical resection followed by postoperative adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. However, resistance to TMZ is one of the factors affecting prognosis. It has been reported that TNF receptor-associated protein 1 (TRAP1) is overexpressed in numerous types of tumor and that interfering with its function may abrogate chemotherapy resistance. TRAP1 inhibitor Gamitrinib triphenylphosphonium (G-TPP) and shRNA were used in the present study to suppress the function of this molecule in glioblastoma multiforme (GBM) cell lines. MTT assay was performed to evaluate the combined effect of G-TPP and TMZ treatment. To investigate the underlying mechanism responsible for this combined effect, the mitochondrial unfolded protein response (mtUPR), mitophagy, mitochondrial fusion and reactive oxygen species (ROS) were quantified using western blotting and immunofluorescence techniques. TMZ treatment induced apoptosis in GBM cells by activating the p53 pathway, whilst simultaneously downregulating mitophagy and enhancing mitochondrial fusion. The latter may occur in order to compensate for the defect caused by downregulated mitophagy. Suppressing the function of TRAP1 disturbed this compensatory mechanism by inducing mtUPR, which resulted in a burst of ROS formation and sensitized the GBM cells to the effects of TMZ treatment. Thus, suppressing the function of TRAP1 sensitized GBM cells to TMZ lysis by inducing mtUPR and the subsequent ROS burst. TRAP1 is therefore considered to be a promising target for GBM therapy.

Prognostic value and immune relevancy of a combined autophagy-, apoptosis- and necrosis-related gene signature in glioblastoma

“…Researchers found that suppressing the function of TRAP1 would benefit temozolomide therapy in GBM in vitro, revealed great potential and practical value in GBM treatment. [ 61 ]. CHP1, MAPK3, PRKAB2 and PRKAG2, these four genes, were rarely focused on.…”

Tumor necrosis factor receptor-associated protein 1 promotes aerobic glycolysis and cisplatin resistance by regulating Wnt/β-catenin signal pathway in lung cancer

“…gastric cancer [15] and other cancers, and is involved in the drug resistance of rectal cancer, glioblastoma and other tumors [16,17] . Giuseppe et al [18] found that silencing TRAP1 could inhibit the progression of cell cycle of thyroid cancer, leading to cell necrosis and promote the sensitivity of cells to chemotherapeutic drugs.…”

“…Studies have shown that TRAP1 is involved in tumor progression by inhibiting apoptosis, promoting drug resistance and in maintaining energy supply under nutrient deprivation conditions [5] . TRAP1 has been reported to be associated with the drug resistance of ovarian cancer [6] , glioblastoma [7] and colon cancer [8] and so on, but whether it is involved in the drug resistance mechanism of lung cancer is still unclear. Therefore, this study intends to explore the relationship between TRAP1 and the energy supply pathway of lung cancer and its cisplatin resistance.…”

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

“…In addition, both cell lines indicated a high degree of migration in the scratch assay. A whole exome sequencing for Jed66_GB indicated the presence of TC-rare damaging COSMIC variants detected in genes that were previously associated with glioblastoma including BCR activator of RhoGEF and GTPase ( BCR ) [ 43 , 44 ], TNF receptor associated protein 1 ( TRAP1 ) [ 45 – 47 ], DNA polymerase delta 1, catalytic subunit ( POLD1 ) [ 48 ], otopetrin 1 ( OTOP1 ) [ 49 ], tyrosine kinase 2 ( TYK2 ) [ 50 ], AT-rich interaction domain 1B ( ARID1B ) [ 51 ], CD48 molecule ( CD48 ) [ 52 ], ubiquitin specific peptidase 18 ( USP18 ) [ 53 ], nuclear receptor corepressor 1 ( NCOR1 ) [ 54 ], NFE2 Like BZIP Transcription Factor 2 ( NFE2L2 ) [ 55 ], and Kinesin Family Member 1A ( KIF1A ) [ 56 ]. For Jed41_GB, exome sequencing showed the presence of TC-rare damaging COSMIC variants detected in glioblastoma-associated genes including TP53 [ 43 , 44 , 57 ], LDL receptor related protein 1B ( LRP1B ) [ 44 , 58 ], adhesion G protein-coupled receptor E5 ( ADGRE5 ) [ 59 ], atrophin 1 ( ATN1 ) [ 60 ], autophagy related 2B ( ATG2B ) [ 61 , 62 ], MYC associated zinc finger protein ( MAZ ) [ 23 , 63 ], WNK lysine deficient protein kinase 1 ( WNK1 ) [ 64 , 65 ], UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) [ 66 ], and UDP glucuronosyltransferase family 1 member A6 ( UGT1A6 ) [ 67 ].…”