Sublethal dose of irradiation enhances invasion of malignant glioma cells through p53-MMP 2 pathway in U87MG mouse brain tumor model

Pei, Jian; Park, In-Ho; Ryu, Hyang‐Hwa; Li, Songyuan; Li, Chunhao; Lim, Sang Chul; Wen, Ming‐Shien; Jang, Won Young; Jung, Shin

doi:10.1186/s13014-015-0475-8

Cited by 31 publications

(24 citation statements)

References 34 publications

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“…AKT is thought to stimulate cell migration through signaling routes [36]. Cellular invasiveness can be inhibited by irradiation, which has been reported before [37]. However, our data shows a modest attenuation of glioma cell mobility through AKT inhibition and shows synergy in only one of the four cell lines tested (Figure 3).…”

Section: Discussionsupporting

confidence: 78%

The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

et al. 2017

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BackgroundGlioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro.MethodsThe effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, −migration and on expression of key proteins in the PI3K-AKT pathway by western blot.ResultsA differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM).ConclusionsThe data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3193-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

et al. 2017

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“…The clinical management of many cancers generally involves the use of radiation therapy, with approximately 50% of cancer patients receiving radiation therapy during the course of their disease [16] . Studies have previously reported that radiation therapy can induce an enhancement of MMP-2 secretion in a wide range of cancer cell types, including lung [17] , pancreas [18] , kidney [19] , and glioma [20] , [21] , [22] . This increase in MMP-2 secretion may assist tumor survival by decreasing apoptosis, inducing proliferation and angiogenesis, as well as promoting invasion [23] .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Radiation and Temozolomide-Induced Invadopodia Activity in Glioma Cells Using FDA-Approved Drugs

Whitehead

Nguyen

Morokoff

et al. 2018

Translational Oncology

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The most common primary central nervous system tumor in adults is the glioblastoma multiforme (GBM). The highly invasive nature of GBM cells is a significant factor resulting in the inevitable tumor recurrence and poor patient prognosis. Tumor cells utilize structures known as invadopodia to faciliate their invasive phenotype. In this study, utilizing an array of techniques, including gelatin matrix degradation assays, we show that GBM cell lines can form functional gelatin matrix degrading invadopodia and secrete matrix metalloproteinase 2 (MMP-2), a known invadopodia-associated matrix-degrading enzyme. Furthermore, these cellular activities were augmented in cells that survived radiotherapy and temozolomide treatment, indicating that surviving cells may possess a more invasive phenotype posttherapy. We performed a screen of FDA-approved agents not previously used for treating GBM patients with the aim of investigating their “anti-invadopodia” and cytotoxic effects in GBM cell lines and identified a number that reduced cell viability, as well as agents which also reduced invadopodia activity. Importantly, two of these, pacilitaxel and vinorelbine tartrate, reduced radiation/temozolomide-induced invadopodia activity. Our data demonstrate the value of testing previously approved drugs (repurposing) as potential adjuvant agents for the treatment of GBM patients to reduce invadopodia activity, inhibit GBM cell invasion, and potentially improve patient outcome.

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“…A study found that the cell adhesion factor E-cadherin and the invading protein MMP-2 could be reduced by chidamide in two kinds of glioma cells (Figures 7-8). The inhibition of the cell adhesion factor E-cadherin [55,56] and the invading protein MMP-2 is a potential way to control tumor cell migration and invasion [57,58].…”

Section: Discussionmentioning

confidence: 99%

Chidamide Inhibits Glioma Cells by Increasing Oxidative Stress via the miRNA-338-5p Regulation of Hedgehog Signaling

Zhou

Liang

Wang³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. Chidamide has a broad spectrum of antitumor activity but its function on glioma remains unknown. The increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS) may control glioma risk by promoting its apoptosis and necrosis. Hedgehog pathway is crucial to glioma cell proliferation and controls ROS production. We aimed to explore the effects of chidamide on the levels of miR-338-5p (glioma cell inhibitor), which may regulate Hedgehog signaling, resulting in the changes of RNS. Materials and Methods. Migration and invasion activities of glioma cells were measured by using the Transwell chamber assay. The expression levels of Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), Desert Hedgehog (Dhh), miR-338-5p, and related molecules were detected by using real-time PCR (RT-PCR) and or Western Blot in U87 and HS683 glioma cells. The effects of chidamide on these molecules were measured by using the miR-338-5p inhibitor or mimics in U87 and HS683 glioma cell lines. ROS and RNS were measured by DCF DA and DAF-FM DA fluorescence. Biomarkers of oxidative stress were measured by using a corresponding kit. Apoptosis and necrosis rates were measured by using flow cytometry. Results. Chidamide inhibited the growth rate, migration, and invasion of human malignant glioma cells and increased the level of miR-338-5p. miR-338-5p inhibitor or mimics increased or inhibited the growth rate of U87 and HS683 glioma cells. Chidamide inhibited the levels of Shh, Ihh, migration protein E-cadherin, and invading protein MMP-2. The increase in the level of Shh and Ihh led to the reduction in the ROS and RNS levels. miR-338-5p inhibitor or mimics also showed a promoting or inhibitory function for the levels of Shh and Ihh. Furthermore, miR-338-5p mimics and inhibitor inhibited or promoted the migration and invasion of the glioma cells (P<0.05). Evaluated levels of miR-338-5p increased oxidative stress level and apoptosis and necrosis rate by regulating the levels of biomarkers of oxidative stress (P<0.05). Conclusion. Chidamide inhibits glioma cells by increasing oxidative stress via the miRNA-338-5p regulation of Hedgehog signaling. Chidamide may be a potential drug in the prevention of glioma development.

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Sublethal dose of irradiation enhances invasion of malignant glioma cells through p53-MMP 2 pathway in U87MG mouse brain tumor model

Cited by 31 publications

References 34 publications

The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

Inhibition of Radiation and Temozolomide-Induced Invadopodia Activity in Glioma Cells Using FDA-Approved Drugs

Chidamide Inhibits Glioma Cells by Increasing Oxidative Stress via the miRNA-338-5p Regulation of Hedgehog Signaling

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