Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

Ram, Ron; Uziel, Orit; Eldan, Orit; Fenig, Eyal; Beery, Einat; Lichtenberg, Shelly; Nordenberg, Yardena; Lahav, Meir

doi:10.1158/1078-0432.ccr-08-0792

Cited by 36 publications

(33 citation statements)

References 47 publications

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“…In the present study, IR induced Akt and ERK1/2 phosphorylation in HT1080 cells within 24 h (especially at 1 h) after irradiation, similar to the findings of previous studies (23,24). Furthermore, we showed that pretreatment with ZOL also inhibited the activation of NF-κB in HT1080 cells, although transcription of NF-κB was activated 1 h after irradiation.…”

Section: Discussionsupporting

confidence: 91%

“…Based on previous reports (23,24) and the present findings, we hypothesized that the cytotoxic effects induced by SE I treatment may depend on the inhibition of Akt and/or ERK1/2 activity by ZOL. To investigate the inhibitory effects of ZOL on Akt and ERK1/2, HT1080 cells were exposed to Akt inhibitor IV, Akt inhibitor VIII, a selective inhibitor of Akt with no effect on PI3K or PDK1, or U0126, a selective MEK inhibitor.…”

Section: The Cytotoxic Effect Was Enhanced By Co-treatment With Ir Ansupporting

confidence: 61%

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Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto

Murata

Kimura

et al. 2012

International Journal of Oncology

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Abstract. Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-κB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

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Section: Discussionsupporting

confidence: 91%

Section: The Cytotoxic Effect Was Enhanced By Co-treatment With Ir Ansupporting

confidence: 61%

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto

Murata

Kimura

et al. 2012

International Journal of Oncology

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“…27 Telomerase expression can be activated during this process. 28 Therefore, ATRX loss and alternative lengthening of telomeres might not be needed for immortalization of radiation-associated tumors.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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“…In addition, hTERT has been found to make cancer cells more resistant against chemotherapeutic agents or radiation therapy via the PI3K/AKT pathway (42), therefore, we speculated that hTERT involved in tumor procession might be via PI3K/AKT pathway. We found that silencing of hTERT inhibited the tyrosine phosphorylation of AKT, and PI3K, which was in agreement with previous results (42), and indicate that knockdown of hTRET inhibits tumor cell growth, to some extent, by suppressing the PI3K/AKT pathway.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of hTERT by siRNA inhibits cervical cancer cell growth in vitro and in vivo

Shi

Zhao

Zhang

et al. 2014

International Journal of Oncology

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Abstract. Human telomerase reverse transcriptase (hTERT)is the catalytic component of telomerase that facilitates tumor cell invasion and proliferation. It has been reported that telomerase and hTERT are significantly upregulated in majority of cancers including cervical cancer, thus, downregulation of hTERT is a promising target in malignant tumor treatment. We established a short interfering RNA (siRNA) targeting hTERT, and transfected it into HeLa cells (a cervical cancer cell line) to investi gate the effect of cell proliferation, apoptosis, migration and invasion in cervical cancer cells. The results showed that siRNA targeting hTERT could effectively knock down hTERT expression, remarkably suppress telomerase activity, cell proliferation, migration and invasion, and induced cell apoptosis of cervical cancers cells in vitro. In addition, we evaluated whether siRNA targeting hTERT affects tumor growth in nude mice, and found that it dramatically inhibited tumorigenesis and growth of mice injected with siRNA targeting hTERT. Furthermore, we also found that knockdown of hTERT was able to significantly suppress constitutive phosphorylation of Akt, PI3K, which might imply that reduction of hTERT inhibited tumor growth via the PI3K/ Akt signaling pathway to some extent. These results suggest that the suppression of hTERT expression by siRNA inhibits cervical cancer cell growth in vitro and in vivo, and may provide a novel target for anticancer gene therapy. IntroductionCervical cancer is caused by a multistep process that involves transformation of the normal cervical epithelium to a preneoplastic cervical intraepithelial neoplasia that is subsequently transformed to invasive cervical cancer (1,2). The incidence and mortality of invasive cervical cancer have steadily decreased (3), and cervical cancer remains the third most common cancer in women worldwide (4) and the leading malignancy in developing countries, accounting for 83% of all cancer cases (5). Although well organized screening and early therapeutic schedules have been carried out, the occurrence of invasive cervical cancer remains high in developing areas (6). Furthermore, as the understanding of key cellular pathways involved in tumor growth has improved, molecular targeted therapies have been widely exploited. Therefore, the development of new therapeutic strategies bases on molecular targeted therapies is necessary to improve survival in patients with cervical cancer.Telomerase plays a key role in conferring immortality to cancer cells through regulation of telomere length (7,8). It synthesizes the telomeric repeats at the ends of chromosomes and replaces the progressively lost end sequences during each cell cycle, allowing cells to escape mortality and continue to proliferate. The reverse transcriptase telomerase is composed of two core components: a ubiquitously expressed RNA component (hTR), and a catalytic subunit human telomerase reverse transcriptase (hTERT) which expression is limited to the formation of a catalytically active enzyme (9) and ...

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Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

Cited by 36 publications

References 47 publications

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

Knockdown of hTERT by siRNA inhibits cervical cancer cell growth in vitro and in vivo

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