Inhibitor of the human telomerase reverse trancriptase (hTERT) gene promoter induces cell apoptosis via a mitochondrial-dependent pathway

Li, Yuyin; Pan, Guoqing; Chen, Yue; Yang, Qian; Tang, Hao; Zhao, Lianbo; Zhao, Long; Cong, Yu‐Sheng; Diao, Aipo; Yu, Peng

doi:10.1016/j.ejmech.2017.12.077

Cited by 25 publications

(7 citation statements)

References 31 publications

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“…Bcl-2 and Ki67 are apoptosis inhibitory factors. Bax and p53 are apoptosis promoting factors [20]. Bax was the first discovered pro-apoptotic factor in the Bcl-2 family [21].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

2019

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Purpose Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) functions in various cancers. We studied the effect and molecular mechanism of TP53AIP1 in breast cancer. Methods The degree of correlation between TP53AIP1 expression and overall survival in patients with breast cancer was obtained from the online The Cancer Genome Atlas database. Six of the TP53AIP1 levels in the tumor and adjacent non-tumor tissues randomly selected from 38 breast cancer patients were determined. Transgenic technology was used to enhance the expression of TP53AIP1 in breast cancer cell lines, MDA-MB-415 and MDA-MB-468, and to observe the effects of gene overexpression on the proliferation, cell cycle, and apoptosis of breast cancer cells. The molecular mechanism of association between cell cycle- and apoptosis-related factors and the phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway was also studied. Results The messenger RNA and protein expression levels of TP53AIP1 in cancer tissues were significantly lower than those in the control group. TP53AIP1 overexpression inhibits cell viability. The mechanism of TP53AIP1 inhibition of proliferation and growth of breast cancer cells includes cell cycle arrest, apoptosis promotion ( p < 0.01), promotion of the expression of cleaved-caspase-3 ( p < 0.01), cleaved-caspase-9 ( p < 0.01), B cell lymphoma/leukemia-2 (Bcl-2)-associated X protein, and p53 ( p < 0.01), and the inhibition of Bcl-2, Ki67, and PI3K/Akt pathways ( p < 0.01). Conclusion TP53AIP1 may be a novel tumor suppressor gene in breast cancer and can potentially be used as an effective target gene for the treatment of breast cancer.

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“…Bcl-2 and Ki67 are apoptosis inhibitory factors. Bax and p53 are apoptosis promoting factors [20]. Bax was the first discovered pro-apoptotic factor in the Bcl-2 family [21].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

2019

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“…When hTERT is overexpressed, the ROS levels are increased through recruitment of the mitochondria. Furthermore, inhibition of hTERT causes mitochondria-dependent apoptosis [85,86]. Inactivation of tumor suppressor genes (e.g., p53) can also increase ROS production.…”

Section: Cancer Microenvironment and Survival Mechanismsmentioning

confidence: 99%

Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts

Hyun

2020

Cancers

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Modest levels of reactive oxygen species (ROS) are necessary for intracellular signaling, cell division, and enzyme activation. These ROS are later eliminated by the body’s antioxidant defense system. High amounts of ROS cause carcinogenesis by altering the signaling pathways associated with metabolism, proliferation, metastasis, and cell survival. Cancer cells exhibit enhanced ATP production and high ROS levels, which allow them to maintain elevated proliferation through metabolic reprograming. In order to prevent further ROS generation, cancer cells rely on more glycolysis to produce ATP and on the pentose phosphate pathway to provide NADPH. Pro-oxidant therapy can induce more ROS generation beyond the physiologic thresholds in cancer cells. Alternatively, antioxidant therapy can protect normal cells by activating cell survival signaling cascades, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in response to radio- and chemotherapeutic drugs. Nrf2 is a key regulator that protects cells from oxidative stress. Under normal conditions, Nrf2 is tightly bound to Keap1 and is ubiquitinated and degraded by the proteasome. However, under oxidative stress, or when treated with Nrf2 activators, Nrf2 is liberated from the Nrf2-Keap1 complex, translocated into the nucleus, and bound to the antioxidant response element in association with other factors. This cascade results in the expression of detoxifying enzymes, including NADH-quinone oxidoreductase 1 (NQO1) and heme oxygenase 1. NQO1 and cytochrome b5 reductase can neutralize ROS in the plasma membrane and induce a high NAD+/NADH ratio, which then activates SIRT1 and mitochondrial bioenergetics. NQO1 can also stabilize the tumor suppressor p53. Given their roles in cancer pathogenesis, redox homeostasis and the metabolic shift from glycolysis to oxidative phosphorylation (through activation of Nrf2 and NQO1) seem to be good targets for cancer therapy. Therefore, Nrf2 modulation and NQO1 stimulation could be important therapeutic targets for cancer prevention and treatment.

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“…Based upon the co‐crystal structure of RAP1/TRF2 complex, Ran et al have developed first‐in‐class triazole‐stapled peptides which block the protein‐protein interaction between RAP1 and TRF2. Furthermore, Li et al also found that compound 36 showed significant inhibition of the promoter activity of the hTERT gene. At present, various small molecules are being developed, and these small molecules can exert antitumor effects in various ways.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 97%

Therapeutic strategies for targeting telomerase in cancer

Chen

Tang

Shi

et al. 2019

Medicinal Research Reviews

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Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

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Inhibitor of the human telomerase reverse trancriptase (hTERT) gene promoter induces cell apoptosis via a mitochondrial-dependent pathway

Cited by 25 publications

References 31 publications

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

Overexpression of Tumor Protein p53-regulated Apoptosis-inducing Protein 1 Regulates Proliferation and Apoptosis of Breast Cancer Cells through the PI3K/Akt Pathway

Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts

Therapeutic strategies for targeting telomerase in cancer

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