Expression and function of ABCG2 and XIAP in glioblastomas

Emery, Ivette F.; Gopalan, Archana; Wood, Stephanie; Chow, Kin Hoe; Battelli, Chiara; George, Joshy; Blaszyk, Hagen; Florman, Jeffrey E.; Yun, Kyuson

doi:10.1007/s11060-017-2422-z

Cited by 52 publications

(29 citation statements)

References 37 publications

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“…X‐linked inhibitor of apoptosis (XIAP), the anti‐apoptotic protein, hinders chemotherapy‐induced apoptosis by the reduction of caspase‐3, ‐7 and ‐9 activation . Glioblastoma patients with high XIAP expression had worse survival rates than those with low XIAP expression . As shown in Figures and , XIAP expression was significantly decreased by imipramine in glioblastoma U87 MG and GBM‐8401 cells.…”

Section: Discussionmentioning

confidence: 93%

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

Hsu

Chiang

Wang

2020

J Cellular Molecular Medi

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Glioblastomas are the most aggressive type of brain tumour, with poor prognosis even after standard treatment such as surgical resection, temozolomide and radiation therapy. The overexpression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in glioblastomas is recognized as an important treatment target. Thus, an urgent need regarding glioblastomas is the development of a new, suitable agent that may show potential for the inhibition of extracellular signal-regulated kinase (ERK)/NF-κB-mediated glioblastoma progression. Imipramine, a tricyclic antidepressant, has anti-inflammatory actions against inflamed glial cells; additionally, imipramine can induce glioblastoma toxicity via the activation of autophagy. However, whether imipramine can suppress glioblastoma progression via the induction of apoptosis and blockage of ERK/NF-κB signalling remains unclear. The main purpose of this study was to investigate the effects of imipramine on apoptotic signalling and ERK/NF-κB-mediated glioblastoma progression by using cell proliferation (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assay), flow cytometry, Western blotting, and cell invasion/migration assay analysis in vitro. The ERK and NF-κB inhibitory capacity of imipramine is detected by NF-κB reporter gene assay and Western blotting. Additionally, a glioblastoma-bearing animal model was used to validate the therapeutic efficacy and general toxicity of imipramine. Our results demonstrated that imipramine successfully triggered apoptosis through extrinsic/intrinsic pathways and suppressed the invasion/migration ability of glioblastoma cells. Furthermore, imipramine effectively suppressed glioblastoma progression in vivo via the inhibition of the ERK/NF-κB pathway. In summary, imipramine is a potential anti-glioblastoma drug which induces apoptosis and has the capacity to inhibit ERK/NF-κB signalling. K E Y W O R D S ERK, extrinsic/intrinsic apoptosis, glioblastoma, imipramine, NF-κB | 3983 HSU et al.

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Section: Discussionmentioning

confidence: 93%

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

Hsu

Chiang

Wang

2020

J Cellular Molecular Medi

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“…XIAP was found to regulate PTEN activity and compartmentalization through its mono- and polyubiquitination in HEK-293-T, MCF-7, and HeLa cells ( 28 ). Emery IF et al utilized 50 GB samples and reported that XIAP overexpression was involved in GSCs development and XIAP could be a useful indicator of patient survival ( 152 ). Lopez, et al showed that XIAP knockdown/inhibitors sensitize GB to temozolomide and other chemotherapy drugs ( 153 ).…”

Section: Aberrant Ubiquitination Disrupts Homeostatic Balance Of Ptenmentioning

confidence: 99%

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

et al. 2020

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Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.

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“…Recently, it have been demonstrated that there were higher expressions of XIAP and Bcl‐2 in the glioblastoma samples than that of normal brain samples that can be allowing the development of new target therapy strategies among GBM patients . XIAP mediates apoptosis resistance and XIAP is a potent inhibitor of cell death that involved the inhibition of specific caspases . Our results indicated BITC decreased the levels of MCL1 and XIAP that may be one of the mechanisms for reduced tumor volumes and weight in xenograft mice model.…”

Section: Discussionmentioning

confidence: 53%

“…XIAP is a protein whose activity mediates chemotherapy resistance and apoptosis resistance . Recently, it have been demonstrated that there were higher expressions of XIAP and Bcl‐2 in the glioblastoma samples than that of normal brain samples that can be allowing the development of new target therapy strategies among GBM patients . XIAP mediates apoptosis resistance and XIAP is a potent inhibitor of cell death that involved the inhibition of specific caspases .…”

Section: Discussionmentioning

confidence: 99%

Benzyl isothiocyanate inhibits human brain glioblastoma multiforme GBM 8401 cell xenograft tumor in nude mice in vivo

Shih

Lin

et al. 2018

Environmental Toxicology

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Benzyl isothiocyanate (BITC), a member of isothiocyanates (ITCs), has been shown to induce cell death in many human cancer cells, but there is no further report to show BITC suppresses glioblastoma multiforme cells in vivo. In the present study, we investigate the effects of BITC on the inhibition of GBM 8401/luc2 cell generated tumor on athymic nude mice. We established a luciferase expressing stable clone named as GBM 8401/luc2. Thirty male mice were inoculated subcutaneously with GBM 8401/luc2 cells to generate xenograft tumor mice model. Group I was treated with 110 μL phosphate-buffered solution plus 10 μL dimethyl sulfoxide, Group II-III with BITC (5 or 10 μmol/100 μL/day, relatively). Mice were given oral treatment of BITC by gavage for 21 days. Results showed that BITC did not affect the body weights. After anesthetized, the photons emitted from mice tumor were detected with Xenogen IVIS imaging system 200 and higher dose of BITC have low total photon flux than that of lower dose of BITC. Results also showed that higher dose of BITC have low total tumor volumes and weights than that of low dose of BITC. Isolated tumors were investigated by immunohistochemical analysis and results showed that BITC at both dose of treatment weakly stained with anti-MCL1 and -XIAP. However, both dose of BITC treatments have strong signals of caspase-3 and Bax. Overall, these data demonstrated that BITC suppressed tumor properties in vivo. Overall, based on these observations, BITC can be used against human glioblastoma multiforme in the future.

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Expression and function of ABCG2 and XIAP in glioblastomas

Cited by 52 publications

References 37 publications

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

Induction of apoptosis through extrinsic/intrinsic pathways and suppression of ERK/NF‐κB signalling participate in anti‐glioblastoma of imipramine

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

Benzyl isothiocyanate inhibits human brain glioblastoma multiforme GBM 8401 cell xenograft tumor in nude mice in vivo

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