Hexokinase 2 is a molecular bridge linking telomerase and autophagy

Roh, Jae Il; Kim, Yujin; Oh, Jahyun; Kim, Yunmi; Lee, Jee Hyun; Lee, Jae‐Hoon; Chun, Kyung–Hee; Lee, Han Woong

doi:10.1371/journal.pone.0193182

Cited by 34 publications

(36 citation statements)

References 51 publications

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“…Because TERT and autophagy gain of function have been observed in several cancers, we proposed a model in which TERT activates autophagy, which is important for generating essential nutrients in a metabolically challenged tumor microenvironment, such as hypoxia (26,27). Thus, we further measured the expression level of LC3-II, a microtubule-associated protein that is a key marker of autophagy, by immunohistochemical staining analysis in 75 PTC patients.…”

Section: Lc3-ii Is Overexpressed In Ptc Tissues and Positively Associmentioning

confidence: 99%

“…Thus, TERT plays a critical role not only in cell survival but also in metabolism. Studies have indicated that gain of TERT function modulates the activity of the mammalian target of rapamycin (mTOR) and induces autophagy, which is required for metabolic rewiring, to scavenge the nutrients that are necessary for fueling cancer cell growth in a challenging tumor microenvironment (26,27). Increasing studies have supported the central role of autophagy in the maintenance and development of various kinds of cancers, including thyroid carcinoma (28).…”

Section: Introductionmentioning

confidence: 99%

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HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress

Song

Chen

Jiao

et al. 2021

Thyroid

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Background: It is important to properly understand the molecular mechanisms of aggressive tumors among papillary thyroid carcinomas (PTCs) that are often the most indolent. Hypoxia inducible factor-1a (HIF-1a), induced by hypoxia, plays pivotal roles in the development and metastasis of the many tumors, including PTCs. Upregulation of telomerase reverse transcriptase (TERT) activity is found in highly invasive PTCs. Further, previous studies have reported that autophagy serves as a protective mechanism to facilitate PTC cell survival. We, therefore, hypothesized that there was a link between HIF-1a, TERT, and autophagy in promoting PTC progression. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of HIF-1a, TERT, and autophagy marker, LC3-II, in matched PTC tumors and corresponding nontumor tissues. Two PTC cell lines (TPC-1 and BCPAP) were used in subsequent cytological function studies. Cell viability, proliferation, apoptosis, migration, and invasion were assessed during hypoxia, genetic enhancement and inhibition of TERT, and chemical and genetic inhibition of autophagy. The protein expression levels of the corresponding biomarkers were determined by Western blotting, and autophagy flow was detected. We characterized the molecular mechanism of PTC cell progression. Results: The protein expression levels of HIF-1a, TERT, and LC3-II were upregulated in PTCs and were significantly correlated with high tumor-node-metastasis stage. Further, an in vitro study indicated that HIF-1a induced by hypoxia functioned as a transcriptional activator by binding with sequences potentially located in the TERT promoter and was positively correlated with the malignant behavior of PTC cell lines. Overexpression of TERT inhibited the kinase activity of mammalian target of rapamycin (mTOR), resulting in the activation of autophagy. Functionally, TERT-induced autophagy provided a survival advantage to PTC cells during hypoxia stress. Conclusions: We identified a novel molecular mechanism involving the HIF-1a/TERT axis, which promoted PTC progression by inducing autophagy through mTOR during hypoxia stress. These findings may provide a basis for the new treatment of aggressive PTCs.

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Section: Lc3-ii Is Overexpressed In Ptc Tissues and Positively Associmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress

Song

Chen

Jiao

et al. 2021

Thyroid

View full text Add to dashboard Cite

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“…The underlying mechanism may be mediated in part by increased mTOR signalling 20 . A recent study reported that TERT can promote autophagy in cancer cells under glucose deprivation through an HK2-mTOR pathway 21 . Our study also revealed that TERT can increase the autophagy activity of myocardial cells after myocardial ischemia-reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Telomerase Reverse Transcriptase Promotes Proliferation, Reduces Apoptosis, and Enhances Autophagy in Cardiomyocytes During Myocardial Ischemia Reperfusion Injury

Fang

Guo

2020

Preprint

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Background: Telomerase reverse transcriptase (TERT) is reported to protect cells from ischemic injury in many diseases. However, the protective role of TERT in myocardial ischemia reperfusion injury (MIRI) remains unclear. The present study aimed to explore the protective roles of TERT in MIRI.Methods: Rat myocardial H9c2 cells were exposed to oxygen and glucose deprivation (OGD) followed by reperfusion to mimic in vivoMIRI. A TERT overexpression model was constructed by adenovirus infection. Cell viability was detected using the CCK8 assay. Immunohistochemicalstaining of Ki67 was used to detect cell proliferation. Apoptosis was detected by TUNEL and flow cytometry analysis of Annexin V-FITC and propidium iodide. Apoptosis-related protein CC3 and autophagy related protein LC3 were detected by western blot analysis. Results:TERT was increased in H9c2 cells after OGD. TERT overexpression promoted the proliferation, attenuated apoptosis, and enhanced autophagy in H9c2 cells after OGD.Conclusions:This study indicates that TERT plays a protective role via promoting proliferation, suppressing apoptosis, and enhancing autophagy in myocardial cells after MIRI. Further study of TERT is expected to reveal new treatment targets for myocardial ischemia-reperfusion injury.

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“…RNA purification and cDNA synthesis were performed as described previously [56]. Briefly, total RNA was isolated using TRIzol reagent (Ambion, Life technologies, USA), following which cDNA was synthesized using a RevertAid First strand cDNA Synthesis Kit (Thermo Fisher Scientific Inc, USA).…”

Section: Rna Purification and Real-time Quantitative Pcr Analysismentioning

confidence: 99%

Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer

et al. 2020

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KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC patients does not respond to currently used therapeutics. Here, we show the tumor-promoting function of a cell cycle-related protein, PIERCE1, in KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, which is particularly observed in KRAS-mutant lung cancers. Analyses of AKT-related genes using microarray, immunoblotting, and real-time quantitative PCR indicated that PIERCE1 negatively regulates the gene expression of the AKT suppressor, TRIB3, through the CHOP pathway, which is a key regulatory pathway for TRIB3 expression. Similarly, in vivo analyses of PIERCE1 depletion in the KRAS mutation-related lung cancer mouse models revealed the suppressive effect of PIERCE1 knockout in urethane-and KRAS G12D-induced lung tumorigenesis with decreased pAKT levels observed in the tumors. Tissue microarrays of human lung cancers indicated the expression of PIERCE1 in 83% of lung cancers and its correlation with pAKT expression. Thus, we illustrate how PIERCE1 depletion may serve as a therapeutic strategy against KRASmutant NSCLC and propose the clinical benefit of PIERCE1.

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Hexokinase 2 is a molecular bridge linking telomerase and autophagy

Cited by 34 publications

References 51 publications

HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress

HIF-1α-Mediated Telomerase Reverse Transcriptase Activation Inducing Autophagy Through Mammalian Target of Rapamycin Promotes Papillary Thyroid Carcinoma Progression During Hypoxia Stress

Telomerase Reverse Transcriptase Promotes Proliferation, Reduces Apoptosis, and Enhances Autophagy in Cardiomyocytes During Myocardial Ischemia Reperfusion Injury

Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer

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