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Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells.

ABSTRACT: Cisplatin is one of the most efficacious antimitotic drugs used in the treatment of a range of malignant tumors. However, treatment failures are common due to the development of chemoresistance. In addition to its telomere maintenance function, telomerase plays a pro-survival role, inducing decreased apoptosis and increased resistance against DNA damage. Elucidation of the molecular mechanisms underlying this effect is critical to improve treatment outcomes. Previously, our group showed higher telomerase reverse transcriptase(TERT) expression in cisplatin resistant osteosarcoma cells. In this study, confocal fluorescence microscopy experiments revealed that TERT translocates from the nucleus to mitochondria in cisplatin treated osteosarcoma cells. We observed decreased apoptosis rate and improved mitochondrial function in TERT-overexpressing cells following cisplatin treatment. Based on these results, we further established that TERT inhibits cisplatin-induced apoptosis independently of telomerase reverse transcriptase activity. Moreover, TERT suppressed cisplatin-induced apoptosis and improved mitochondrial function via alleviating intracellular ROS in osteosarcoma cells. Our finding that TERT shuttles from the nucleus to the mitochondrion in response to cisplatin treatment and inhibits cisplatin-induced apoptosis in osteosarcoma cells may be especially important to overcome drug resistance.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC5539325 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells.

Zhang Zhengpei Z Yu Ling L Dai Guo G Xia Kezhou K Liu Gaiwei G Song Qi Q Tao Chunjie C Gao Tian T Guo Weichun W

Scientific reports 20170801 1

Cisplatin is one of the most efficacious antimitotic drugs used in the treatment of a range of malignant tumors. However, treatment failures are common due to the development of chemoresistance. In addition to its telomere maintenance function, telomerase plays a pro-survival role, inducing decreased apoptosis and increased resistance against DNA damage. Elucidation of the molecular mechanisms underlying this effect is critical to improve treatment outcomes. Previously, our group showed higher t ...[more]

PMID: 28765565

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Project description:BackgroundAngiogenesis is an endogenous repair mechanism following hypoxic-ischemic brain damage (HIBD). Interestingly, recent studies have shown that angiogenesis can be regulated by telomerase reverse transcriptase (TERT), a critical component of telomerase. As telomerase reverse transcriptase can promote angiogenesis after stroke, we hypothesized that it could also promote angiogenesis after HIBD. To test this hypothesis, we developed in vivo and in vitro HIBD models in neonatal rats.MethodsTERT was overexpressed by lentivirus and adenovirus infection, and levels were measured using quantitative real-time polymerase chain reaction. We used a cell counting kit to quantify the proliferation rate of brain microvascular endothelial cells (BMECs), and immunofluorescence staining to measure CD34 expression levels. A microvessel formation assay was used to evaluate angiogenesis. Blood-brain barrier (BBB) integrity was assessed using immunohistochemical staining for ZO-1 and Evans Blue staining. Lastly, the expression level of Notch-1 was measured by western blotting.ResultsOverexpression of TERT promoted the proliferation of BMECs after hypoxic-ischemic damage in vitro. TERT overexpression increased the formation of microvessels in the neonatal brain after HIBD both in vivo and in vitro. Overexpression of TERT improved BBB integrity in the brains of neonatal rats after HIBD. In addition, the expression level of Notch-1 was increased in BMECs following oxygen glucose deprivation, and overexpression of TERT further increased Notch-1 expression levels in BMECs following oxygen glucose deprivation.DiscussionOur results reveal that telomerase reverse transcriptase promotes angiogenesis and maintains the integrity of the blood-brain barrier after neonatal hypoxic-ischemic brain damage. Furthermore, the Notch-1 signaling pathway appears to contribute to the angiogenic function of telomerase reverse transcriptase. This protective effect of telomerase reverse transcriptase opens new horizons for future investigations aimed at uncovering the full potential of telomerase reverse transcriptase as a promising new target for the treatment of hypoxic-ischemic encephalopathy.

Dataset Information

Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells.

Publications

Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells.

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