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Silencing of the hTERT gene through RNA interference induces apoptosis via bax/bcl-2 in human glioma cells.

ABSTRACT: Glioma cells are characterized by their invasiveness and resistance to conventional therapeutics. The downregulation of human telomerase reverse transcriptase (hTERT) can lead to decreased cell proliferation and/or the induction of apoptotic cell death in cancer cells but has rarely been reported in glioma cells. Here, we assessed the effect of the silencing of the hTERT gene on cell apoptosis and its possible molecular mechanism in T98G glioma cells. We found that the silencing of the hTERT gene in T98G cells significantly decreased cell proliferation and telomerase activity, increased the number of cells in G1 phase and decreased the number of cells in S phase, and induced apoptosis via decreasing the protein level of bcl-2 and c-myc and increasing the protein levels of bax and p53.

SUBMITTER: Wang T

PROVIDER: S-EPMC3583528 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Silencing of the hTERT gene through RNA interference induces apoptosis via bax/bcl-2 in human glioma cells.

Wang Tuo T Xue Yan Y Wang Maode M Sun Qiang Q

Oncology reports 20120806 4

Glioma cells are characterized by their invasiveness and resistance to conventional therapeutics. The downregulation of human telomerase reverse transcriptase (hTERT) can lead to decreased cell proliferation and/or the induction of apoptotic cell death in cancer cells but has rarely been reported in glioma cells. Here, we assessed the effect of the silencing of the hTERT gene on cell apoptosis and its possible molecular mechanism in T98 ...[more]

PMID: 22895663

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Project description:In more than 90% of cancers including glioma, telomere elongation reverse transcriptase (hTERT) is overexpressed. In the present study, we sought to explore whether matrix metalloproteinase-9 (MMP-9) shRNA could alter hTERT-mediated proliferation in glioma cells. MMP-9 shRNA induced senescence and apoptosis in glioma cells by inhibiting hTERT expression and telomere activity. MMP-9 silencing decreased oncogenic c-Myc expression (hTERT activator), whereas the expression of the c-Myc antagonist MAD increased drastically (hTERT repressor); both c-Myc and MAD are transcription factors for hTERT. In addition, MMP-9 suppression turns the switch from c-Myc/MAX to MAD/MAX heterodimer binding to the hTERT promoter as determined by chromatin immunoprecipitation assay. We also show that silencing MAD via siRNA restored hTERT expression and inhibited senescence in glioma cells. MMP-9 transcriptional suppression decreased the expression of FAK, phospho FAK and ?1 integrin in glioma xenograft cells. Further, MMP-9 suppression decreased the interaction of ?1 integrin/FAK and also MMP-9/?1 integrin as confirmed by immunoprecipitation analysis. Studies with either function blocking ?1 integrin or FAK shRNA indicate that suppression of MMP-9 decreased ?1 integrin-mediated induction of FAK, which led to decreased hTERT expression. Moreover, 4910 and 5310 glioma xenograft tissue sections from mice treated with MMP-9 shRNA showed reduced expression of FAK/c-Myc and elevated MAD levels. Decreased co-localization of ?1 integrin and MMP-9 was associated with MMP-9-suppressed tumor sections. Further, immunoprecipitation analysis showed decreased association of proteins involved in telomere end repair in MMP-9 shRNA-treated glioma cells. Elevated levels of p73 and TRAIL and the results of the FACS analysis show induction of apoptosis in MMP-9-silenced glioma cells. Taken together, these data provide new insights into the mechanisms underlying MMP-9-mediated hTERT expression in glioma proliferation.

Project description:Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110?-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.

Dataset Information

Silencing of the hTERT gene through RNA interference induces apoptosis via bax/bcl-2 in human glioma cells.

Publications

Silencing of the hTERT gene through RNA interference induces apoptosis via bax/bcl-2 in human glioma cells.

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