The Regulation of ROS‐ and BECN1‐Mediated Autophagy by Human Telomerase Reverse Transcriptase in Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with high morbidity and mortality. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, is overexpressed in most cancers including GBM. It is well known that hTERT can compensate telomere shortening to immortalize cells. However, in addition to the canonical function, hTERT has the roles beyond canonical telomere maintenance. To further understand the effects of hTERT on glioblastoma progression, we investigated the role of hTERT in regulating autophagy—a conserved pathway, by which cells deliver cellular organic material and impaired organelles to the lysosomes for degradation and recycle these cargos to produce energy under a stressful condition. Our results showed that downregulation of hTERT impaired autophagy levels by suppressing BECN1/beclin-1 and induced an increase of reactive oxygen species (ROS), which resulted in cell death ultimately. On the contrary, overexpression of BECN1 or treating cells with the antioxidant N-acetylcysteine (NAC) could restore the survival of hTERT knockdown cells. Our study will provide an additional basis of telomerase-targeting therapy for future clinical anticancer treatment.

A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

“…Because autophagy is a key molecular mechanism for immune function and telomerase has been shown activate autophagy in different cells types 72-75 , we hypothesised that gut macrophage autophagy would be affected in the absence of telomerase. Our data show that there is a significant decrease in autophagosomes, as assessed by LC3B puncta, in the mpeg + gut cell population with old age, which again is accelerated in the absence of telomerase ( Fig 4D), D1) ).…”

“…Instead, they may be better explained by non-canonical functions of telomerase. Telomerase is not only capable of restoring telomeres (canonical function) but also of performing non-canonical functions involved in the regulation of cell survival, inflammation and autophagy [72][73][74][75] (recently reviewed here 21 ). Here, we identified a telomerase-dependent decrease in autophagosomes (LC3B puncta) in gut mpeg + cells with ageing.…”

“…Our results show that there is a significant decrease in the numbers of mpeg + cells in the gut in old age, but that this is not significantly accelerated in the absence of telomerase, at least at the young age that our work is focusing on. Because autophagy is a key molecular mechanism for immune function and telomerase has been shown activate autophagy in different cells types [72][73][74][75] , we hypothesised that gut macrophage autophagy would be affected in the absence of telomerase. Our data…”

Antioxidant Effects of Irisin in Liver Diseases: Mechanistic Insights

“…Telomerase also participates in the regulation of autophagy. It is reported that downregulation of telomerase activity impaired autophagy function, leading to the overproduction of ROS [66]. Moreover, Green et al also demonstrated that telomerase participated in the cellular response to oxidative stress by regulating autophagy, giving a further verification about interaction between telomerase and autophagy [67].…”

Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α

“…The interplay between telomerase and autophagy was shown in several studies on cancer. Ding et al showed that downregulation of hTERT reduced autophagy and decreased BECN1 (Beclin 1, coiled-coil, moesin-like BCL2-interacting protein) in glioblastoma cells [106]. These cells displayed enhanced levels of ROS and ultimately died.…”