EGFR inhibitor BIBU induces apoptosis and defective autophagy in glioma cells

Ghildiyal, Ruchi; Dixit, Deobrat; Sen, Ellora

doi:10.1002/mc.21938

Cited by 11 publications

(10 citation statements)

References 56 publications

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“…MDGI has been previously shown to affect EGFR trafficking (Nevo et al , ), inhibition of which can induce glioma cell apoptosis (Ghildiyal et al , ; Kaluzova et al , ). Thus, we investigated the EGFR expression and pathway activity in glioma cells.…”

Section: Resultsmentioning

confidence: 99%

“…These results demonstrate a dose-dependent effect of MDGI silencing on glioblastoma cell growth and viability. MDGI has been previously shown to affect EGFR trafficking (Nevo et al, 2009), inhibition of which can induce glioma cell apoptosis (Ghildiyal et al, 2013;Kaluzova et al, 2015). Thus, we investigated the EGFR expression and pathway activity in glioma cells.…”

Section: Mdgi Silencing Reduces Glioblastoma Cell Viabilitymentioning

confidence: 98%

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Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

et al. 2019

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The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor ( MDGI / FABP 3 ) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient‐derived glioma cells via lysosomal membrane permeabilization ( LMP ). In a preclinical model, treatment of glioma‐bearing mice with an antihistaminergic LMP ‐inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re‐positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo‐resistant glioma cells from sustaining disease progression and recurrence.

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Section: Resultsmentioning

confidence: 99%

Section: Mdgi Silencing Reduces Glioblastoma Cell Viabilitymentioning

confidence: 98%

Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

et al. 2019

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“…Moreover, EGFR activation protects against ultraviolet-induced apoptosis in cultured mouse dendritic cells through the induction of the LKB1̸AMPK pathway (24,25). The EGFR inhibitor BIBU may induce apoptosis and prevent execution of autophagy in glioma cells via the inhibition of the pro-survival pathways AKT̸mTOR and gp130̸JAK̸STAT3 (26). The MAPK pathway may transmit signals from the receptor to the nucleus through a series of intermediate proteins, including Ras, Raf, MEK and ERK.…”

Section: Egfr and Autophagy Regulationmentioning

confidence: 99%

Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

Sui

Kong

Zhu

et al. 2013

Molecular and Clinical Oncology

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Epidermal growth factor receptor (EGFR) somatic mutations are found in the majority of non-small-cell lung cancers (NSCLCs) and patients with NSCLC who harbor EGFR mutations have been shown to exhibit increased sensitivity to the small-molecule EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, the majority of tumors develop acquired resistance to EGFR-TKIs after a median of 10-16 months, which limits the clinical efficacy of these drugs. Autophagy, an important homeostatic cellular recycling mechanism, has emerged as a potential target for the acquired resistance phenotype. Recently, several studies demonstrated that autophagy may be induced in a dose-dependent manner by treatment of multiple cancer cell lines with EGFR-TKIs . Furthermore, it was recently reported that autophagy, as a cytoprotective response, may be activated by EGFR-TKIs in lung cancer cells and that the inhibition of autophagy enhanced the cytotoxic effect of EGFR-TKIs. In this review, we aimed to focus on the association between resistance to EGFR-TKIs and autophagy, and assess whether autophagy inhibition represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients.

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“…The expression of γ H2AX (green) was analyzed using Zeiss ApoTome Imager.Z1 as described. 56 DNA counterstaining was performed with 4,6-diamidino-2-phenylindole (DAPI) (Vector).…”

Section: Methodsmentioning

confidence: 99%

ATM-NFκB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFα

et al. 2013

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Gliomas are resistant to radiation therapy, as well as to TNFα induced killing. Radiation-induced TNFα triggers Nuclear factor κB (NFκB)-mediated radioresistance. As inhibition of NFκB activation sensitizes glioma cells to TNFα-induced apoptosis, we investigated whether TNFα modulates the responsiveness of glioma cells to ionizing radiation-mimetic Neocarzinostatin (NCS). TNFα enhanced the ability of NCS to induce glioma cell apoptosis. NCS-mediated death involved caspase-9 activation, reduction of mitochondrial copy number and lactate production. Death was concurrent with NFκB, Akt and Erk activation. Abrogation of Akt and NFκB activation further potentiated the death inducing ability of NCS in TNFα cotreated cells. NCS-induced p53 expression was accompanied by increase in TP53-induced glycolysis and apoptosis regulator (TIGAR) levels and ATM phosphorylation. siRNA-mediated knockdown of TIGAR abrogated NCS-induced apoptosis. While DN-IκB abrogated NCS-induced TIGAR both in the presence and absence of TNFα, TIGAR had no effect on NFκB activation. Transfection with TIGAR mutant (i) decreased apoptosis and γH2AX foci formation (ii) decreased p53 (iii) elevated ROS and (iv) increased Akt/Erk activation in cells cotreated with NCS and TNFα. Heightened TIGAR expression was observed in GBM tumors. While NCS induced ATM phosphorylation in a NFκB independent manner, ATM inhibition abrogated TIGAR and NFκB activation. Metabolic gene profiling indicated that TNFα affects NCS-mediated regulation of several genes associated with glycolysis. The existence of ATM-NFκB axis that regulate metabolic modeler TIGAR to overcome prosurvival response in NCS and TNFα cotreated cells, suggests mechanisms through which inflammation could affect resistance and adaptation to radiomimetics despite concurrent induction of death.

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EGFR inhibitor BIBU induces apoptosis and defective autophagy in glioma cells

Cited by 11 publications

References 56 publications

Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

ATM-NFκB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFα

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