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Carbenoxolone enhances TRAIL-induced apoptosis through the upregulation of death receptor 5 and inhibition of gap junction intercellular communication in human glioma.

ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been used extensively in cancer therapy. However, more than half of glioblastoma multiforme are insensitive to the apoptotic effect of TRAIL. Improvement in therapeutic modalities that enhances the efficacy of TRAIL in glioma is much sought after. In this study, we combined the tumor selectivity of TRAIL and tumor-homing properties of mesenchymal stem cells (MSC) with gap junction (GJ) inhibitory effect of carbenoxolone (CBX) to target orthotopic glioma. MSC were engineered to express TRAIL (MSC-TRAIL) by incorporating the secretable trimeric form of TRAIL into a Herpes Simplex Virus (HSV) type I amplicon vector. Our results showed that combined treatment of MSC-TRAIL and CBX enhanced glioma cell death, especially in three primary human glioma isolates, of which two of those are marginally sensitive to TRAIL. CBX enhanced TRAIL-induced apoptosis through upregulation of death receptor 5, blockade of GJ intercellular communication, and downregulation of connexin 43. Dual arm therapy using TRAIL and CBX prolonged the survival of treated mice by ~27% when compared with the controls in an intracranial glioma model. The enhanced efficacy of TRAIL in combination with CBX coupled with the minimal cytotoxic nature of CBX suggested a favorable clinical usage of this treatment regimen.

SUBMITTER: Yulyana Y

PROVIDER: S-EPMC3685394 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Carbenoxolone enhances TRAIL-induced apoptosis through the upregulation of death receptor 5 and inhibition of gap junction intercellular communication in human glioma.

Yulyana Yulyana Y Endaya Berwini B BB Ng Wai H WH Guo Chang M CM Hui Kam M KM Lam Paula Y P PY Ho Ivy A W IA

Stem cells and development 20130326 13

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been used extensively in cancer therapy. However, more than half of glioblastoma multiforme are insensitive to the apoptotic effect of TRAIL. Improvement in therapeutic modalities that enhances the efficacy of TRAIL in glioma is much sought after. In this study, we combined the tumor selectivity of TRAIL and tumor-homing properties of mesenchymal stem cells (MSC) with gap junction (GJ) inhibitory effect of carbenoxolone (CBX) to ...[more]

PMID: 23428290

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Project description:UNLABELLED:Gap junctional intercellular communication (GJIC) plays a critical role in the regulation of tissue homeostasis and carcinogenesis and is modulated by the levels, subcellular localization, and posttranslational modification of gap junction proteins, the connexins (Cx). Here, using oval cell-like rat liver epithelial cells, we demonstrate that the RNA-binding protein HuR promotes GJIC through two mechanisms. First, HuR silencing lowered the levels of Cx43 protein and Cx43 messenger RNA (mRNA), and decreased Cx43 mRNA half-life. This regulation was likely due to the direct stabilization of Cx43 mRNA by HuR, because HuR associated directly with Cx43 mRNA, a transcript that bears signature adenylate-uridylate-rich (AU-rich) and uridylate-rich (U-rich) sequences in its 3'-untranslated region. Second, HuR silencing reduced both half-life and the levels of beta-catenin mRNA, also a target of HuR; accordingly, HuR silencing lowered the levels of whole-cell and membrane-associated beta-catenin. Coimmunoprecipitation experiments showed a direct interaction between beta-catenin and Cx43. Small interfering RNA (siRNA)-mediated depletion of beta-catenin recapitulated the effects of decreasing HuR levels: it attenuated GJIC, decreased Cx43 levels, and redistributed Cx43 to the cytoplasm, suggesting that depletion of beta-catenin in HuR-silenced cells contributed to lowering Cx43 levels at the membrane. Finally, HuR was demonstrated to support GJIC after exposure to a genotoxic agent, doxorubicin, or an inducer of differentiation processes, retinoic acid, thus pointing to a crucial role of HuR in the cellular response to stress and in physiological processes modulated by GJIC. CONCLUSION:HuR promotes gap junctional intercellular communication in rat liver epithelial cells through two related regulatory processes, by enhancing the expression of Cx43 and by increasing the expression of beta-catenin, which, in turn, interacts with Cx43 and is required for proper positioning of Cx43 at the plasma membrane.

Dataset Information

Carbenoxolone enhances TRAIL-induced apoptosis through the upregulation of death receptor 5 and inhibition of gap junction intercellular communication in human glioma.

Publications

Carbenoxolone enhances TRAIL-induced apoptosis through the upregulation of death receptor 5 and inhibition of gap junction intercellular communication in human glioma.

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