Abstract
Cellular senescence is characterized by permanent cell cycle arrest, triggered by a variety of stresses, such as telomerase inhibition, and it is recognized as a tumor-suppressor mechanism. In recent years, telomerase has become an important therapeutic target in several cancers; inhibition of telomerase can induce senescence via the DNA damage response (DDR). Pterostilbene (PT), a dimethyl ether analog of resveratrol, possesses a variety of biological functions, including anticancer effects; however, the molecular mechanisms underlying these effects are not fully understood. In this study, we investigated the possible mechanisms of PT-induced senescence through telomerase inhibition in human non-small cell lung cancer cells and delineated the role of p53 in senescence. The results indicated that PT-induced senescence is characterized by a flattened morphology, positive staining for senescence-associated-β galactosidase activity, and the formation of senescence-associated heterochromatic foci. Telomerase activity and protein expression was significantly decreased in H460 (p53 wild type) cells compared with H1299 (p53 null) cells and p53 knockdown H460 cells (H460-p53-). A more detailed mechanistic study revealed that PT-induced senescence partially occurred via a p53-dependent mechanism, triggering inhibition of telomerase activity and protein expression, and leading to the DDR, S phase arrest and, finally, cellular senescence. This study is the first to explore the novel anticancer mechanism of PT senescence induction via the inhibition of telomerase in lung cancer cells.
Highlights
Cellular senescence is the specific phenotype in which cells lose the ability to proliferate in response to various mitogens or cellular stresses such as DNA damage, telomere shortening and oxidative stress.[1]
The results indicated that lung cancer cells entered ‘prolonged arrest’ through the loss of proliferative potential after PT treatment
We further confirmed whether the inhibition of human telomerase reverse transcriptase (hTERT) activity and expression is mediated by p53, and the results revealed that hTERT expression and activity were reduced in H1299-p53+ cells similar to H460 cells treated with PT (Figures 4c and d)
Summary
Cellular senescence is the specific phenotype in which cells lose the ability to proliferate in response to various mitogens or cellular stresses such as DNA damage, telomere shortening and oxidative stress.[1]. Potential intervention targets for the pro-senescence approach are telomerase inhibition, p53 activation, modulation of the cell cycle and the activation of phosphatase and tensin homolog.[5] Telomerase is an enzyme that is responsible for the maintenance of telomeres, essential structures that cap chromosome ends and protect chromosome stability.[6] Human telomeres are composed of tandem copies of TTAGGG in DNA repeat sequences and associated proteins, which together form a protective capping complex. Our current study investigated the potency of PT-induced senescence by targeting telomerase in lung cancer cells with different p53 phenotypes
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