Sensitization of Glioma Cells by X-Linked Inhibitor of Apoptosis Protein Knockdown

Lopez, Patricia L.C.; Filippi-Chiela, Eduardo Cremonese; Silva, Andrew O.; Cordero, Elvira Alicia Aparicio; Garcia-Santos, Daniel; Pelegrini, Alessandra Luíza; Reder, Gleice M.; Barbieri, Nicolle Lima; Lenz, Guido

doi:10.1159/000337978

Cited by 15 publications

(7 citation statements)

References 79 publications

(44 reference statements)

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“…XIAP is the strongest apoptosis-inhibitor in the IAPs family, which is located at Xq25 and is critically involved in the tumor-tolerant radiotherapy and chemotherapy [ 23 , 24 ]. Over the past decades, growing evidence has shown that XIAP functions to promote the tumor growth and to inhibit the apoptosis in a variety of tumor cells [ 25 – 27 ].…”

Section: Discussionmentioning

confidence: 99%

CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186

et al. 2015

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The long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) is a novel gene that activated early in colorectal neoplasia, but it is also up-regulated in many other solid tumors. Herein, the function and underlying mechanism of CRNDE in regulating glioma stem cells (GSCs) were investigated. We found that CRNDE expression was up-regulated while miR-186 expression was down-regulated in GSCs. Overexpression of CRNDE could promote the cellular proliferation, migration, invasion and inhibit the apoptosis in GSCs. Overexpression of miR-186 exerted functions of inhibiting the proliferation, migration and invasion of GSCs and promoting apoptosis. And CRNDE decreased the expression levels of XIAP and PAK7 by binding to miR-186 and negatively regulating it. In addition, miR-186 binded to XIAP and PAK7 3′UTR region, and decrease the expression of them, thus regulating the expression levels of downstream target proteins such as caspase 3, BAD, cyclin D1 and MARK2. The in vivo effect of CRNDE and miR-186 showed that the tumor formation rate was minimum in tumor-bearing nude mice with the knockdown of CRNDE and the overexpression of miR-186. In conclusion, CRNDE played an oncogenic role of GSCs through the negative regulation of miR-186. Both CRNDE and miR-186 could be regarded as potential targets in the glioma therapy.

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Section: Discussionmentioning

confidence: 99%

CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186

et al. 2015

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“…Images were analyzed using Image J Software, for the acquisition of the nuclear area and the parameters of nuclear irregularity (roundness, aspect, radius ratio and area/box, which are grouped in an index, named the nuclear irregularity index (NII)). The plot of nuclear area per NII permits the separation of different nuclear populations and the inference of different cell death and growth inhibition mechanisms such as apoptosis (small and regular nuclei—SR nuclei), senescence (large and regular nuclei—LR nuclei) and irregular nuclei (I nuclei) [55,56]. …”

Section: Methodsmentioning

confidence: 99%

Dexamethasone and Azathioprine Promote Cytoskeletal Changes and Affect Mesenchymal Stem Cell Migratory Behavior

et al. 2015

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Glucocorticoids and immunosuppressive drugs are commonly used to treat inflammatory disorders, such as inflammatory bowel disease (IBD), and despite a few improvements, the remission of IBD is still difficult to maintain. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have emerged as regulators of the immune response, and their viability and activation of their migratory properties are essential for successful cell therapy. However, little is known about the effects of immunosuppressant drugs used in IBD treatment on MSC behavior. The aim of this study was to evaluate MSC viability, nuclear morphometry, cell polarity, F-actin and focal adhesion kinase (FAK) distribution, and cell migratory properties in the presence of the immunosuppressive drugs azathioprine (AZA) and dexamethasone (DEX). After an initial characterization, MSCs were treated with DEX (10 μM) or AZA (1 μM) for 24 hrs or 7 days. Neither drug had an effect on cell viability or nuclear morphometry. However, AZA treatment induced a more elongated cell shape, while DEX was associated with a more rounded cell shape (P < 0.05) with a higher presence of ventral actin stress fibers (P < 0.05) and a decrease in protrusion stability. After 7 days of treatment, AZA improved the cell spatial trajectory (ST) and increased the migration speed (24.35%, P < 0.05, n = 4), while DEX impaired ST and migration speed after 24 hrs and 7 days of treatment (-28.69% and -25.37%, respectively; P < 0.05, n = 4). In conclusion, our data suggest that these immunosuppressive drugs each affect MSC morphology and migratory capacity differently, possibly impacting the success of cell therapy.

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“…Similarly, it was demonstrated that resveratrol sensitizes tamoxifen in estrogen receptor resistance breast cancer models that show epithelial-to-mesenchymal transition [ 315 ]. In a glioma model, resveratrol was shown to suppress X linked inhibitor of apoptotic proteins [ 316 ]. While Díaz-Chávez [ 317 ] utilized a proteomic approach to investigate the mechanism of resveratrol mediated chemosensitization and highlighted the role of hsp27 (at least in the model they tested).…”

Section: Role Of Different Natural Compounds (Phytochemicals) Agamentioning

confidence: 99%

Broad targeting of resistance to apoptosis in cancer

Mohammad

Muqbil

Lowe³

et al. 2015

Seminars in Cancer Biology

606

370

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Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

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Sensitization of Glioma Cells by X-Linked Inhibitor of Apoptosis Protein Knockdown

Cited by 15 publications

References 79 publications

CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186

CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186

Dexamethasone and Azathioprine Promote Cytoskeletal Changes and Affect Mesenchymal Stem Cell Migratory Behavior

Broad targeting of resistance to apoptosis in cancer

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