Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma

Wang, Zengguang; Sun, Jikui; Li, Xue; Shen, Yang; Yue, Shuyuan; Zhang, Jianning; Yang, Xuejun; Zhu, Tao; Jiang, Rongcai; Yang, Weidong

doi:10.3892/or.2013.2240

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…Thus, we further analyzed which signaling pathways and apoptotic factors are altered upon integrin silencing. Our data revealed that integrin αVβ3 transmits signals through pFAK, pSrc and pAkt, which is in line with results showing that Src silencing enhanced the cytotoxic effect of TMZ in LN229 cells [44]. The same inhibition of FAK/Src/Akt in glioma cells was also shown upon CGT [45].…”

Section: Discussionsupporting

confidence: 89%

Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair

et al. 2016

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Integrins have been suggested as possible targets in anticancer therapy. Here we show that knockdown of integrins αVβ3, αVβ5, α3β1 and α4β1 and pharmacological inhibition using a cyclo-RGD integrin αVβ3/αVβ5 antagonist sensitized multiple high-grade glioma cell lines to temozolomide (TMZ)-induced cytotoxicity. The greatest effect was observed in LN229 cells upon integrin β3 silencing, which led to inhibition of the FAK/Src/Akt/NFκB signaling pathway and increased formation of γH2AX foci. The integrin β3 knockdown led to the proteasomal degradation of Rad51, reduction of Rad51 foci and reduced repair of TMZ-induced DNA double-strand breaks by impairing homologous recombination efficiency. The down-regulation of β3 in Rad51 knockdown (LN229-Rad51kd) cells neither further sensitized them to TMZ nor increased the number of γH2AX foci, confirming causality between β3 silencing and Rad51 reduction. RIP1 was found cleaved and IκBα significantly less degraded in β3-silenced/TMZ-exposed cells, indicating inactivation of NFκB signaling. The anti-apoptotic proteins Bcl-xL, survivin and XIAP were proteasomally degraded and caspase-3/−2 cleaved. Increased H2AX phosphorylation, caspase-3 cleavage, reduced Rad51 and RIP1 expression, as well as sustained IκBα expression were also observed in mouse glioma xenografts treated with the cyclo-RGD inhibitor and TMZ, confirming the molecular mechanism in vivo. Our data indicates that β3 silencing in glioma cells represents a promising strategy to sensitize high-grade gliomas to TMZ therapy.

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Section: Discussionsupporting

confidence: 89%

Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair

et al. 2016

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“…27 Alterations to MGMT levels or mismatch repair status have been proposed as the main drivers for the development of this resistance, 13 but activation of the Akt pathway has also been proposed and linked with Src levels. 45 A study by Sun et al 41 showed that TMZ-resistant glioma cells were associated with changes in actin cytoskeleton-related proteins and increased adhesion and migration properties that are known to be functionally linked to invadopodia-associated mechanisms. Therefore, the involvement of the EGFR-Src-(PI3)/AKT pathway in glioma invasion, invadopodia formation/activity, and treatment resistance (radiotherapy/TMZ) highlights the potential importance of this signaling axis as a therapeutic avenue in targeting glioma invasion through invadopodia after radiotherapy and TMZ treatment.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of invadopodia activity in glioma cells by sublethal doses of irradiation and temozolomide

Mao

Whitehead

Paradiso

et al. 2018

Journal of Neurosurgery

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OBJECTIVE Glioblastoma is the most common primary central nervous system tumor in adults. These tumors are highly invasive and infiltrative and result in tumor recurrence as well as an extremely poor patient prognosis. The current standard of care involves surgery, radiotherapy, and chemotherapy. However, previous studies have suggested that glioblastoma cells that survive treatment are potentially more invasive. The goal of this study was to investigate whether this increased phenotype in surviving cells is facilitated by actin-rich, membrane-based structures known as invadopodia. METHODS A number of commercially available cell lines and glioblastoma cell lines obtained from patients were initially screened for the protein expression levels of invadopodia regulators. Gelatin-based zymography was also used to establish their secretory protease profile. The effects of radiation and temozolomide treatment on the glioblastoma cells were then investigated with cell viability, Western blotting, gelatin-based zymography, and invadopodia matrix degradation assays. RESULTS The authors' results show that the glioma cells used in this study express a number of invadopodia regulators, secrete MMP-2, and form functional matrix-degrading invadopodia. Cells that were treated with radiotherapy and temozolomide were observed to show an increase primarily in the activation of MMP-2. Importantly, this also resulted in a significant enhancement in the invadopodia-facilitated matrix-degrading ability of the cells, along with an increase in the percentage of cells with invadopodia after radiation and temozolomide treatment. CONCLUSIONS The data from this study suggest that the increased invasive phenotype that has been previously observed in glioma cells posttreatment is mediated by invadopodia. The authors propose that if the formation or activity of these structures can be disrupted, they could potentially serve as a viable target for developing novel adjuvant therapeutic strategies that can be used in conjunction with the current treatment protocols in combatting the invasive phenotype of this deadly disease.

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“…The Cx43 C-terminus interacts with a number of signaling molecules including c-Src, protein kinase C, AKT serine/threonine kinase, and mitogen-activated protein kinase to name a few (reviewed in [63 • ]). These interactions can also affect the phosphorylation status of Cx43 and consequently regulate its degradation, subcellular localization, and channel assembly processes, in addition to potentially mediating GBM resistance to TMZ [64,65]. Independent of channel activity, we have also found that aCT1 sensitizes GBM to TMZ in association with suppression of AKT activity [6 •• ].…”

Section: Therapeutic Opportunity For Connexin43 Peptidomimeticsmentioning

confidence: 99%

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Grek

Sheng

Naus

et al. 2018

Current Opinion in Pharmacology

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Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra-tumor and inter-tumor heterogeneity make it difficult to clearly define specific populations for Cx43-targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient-derived stem cells, could provide opportunities for patient-specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.

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Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma

Cited by 8 publications

References 23 publications

Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair

Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair

Enhancement of invadopodia activity in glioma cells by sublethal doses of irradiation and temozolomide

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

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