P53-dependent downregulation of hTERT protein expression and telomerase activity induces senescence in lung cancer cells as a result of pterostilbene treatment.

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.

• Authors: Rong-Jane Chen, Pei-Hsuan Wu, Chi-Tang Ho, Tzong-Der Way, Min-Hsiung Pan, Hsiu-Min Chen, Yuan-Soon Ho, Ying-Jan Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 8 Pg. e2985 (08 10 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 28796247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Stilbenes
• Tumor Suppressor Protein p53
• pterostilbene
• Telomerase

Topics

• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (metabolism)
• Cell Line, Tumor
• Cellular Senescence (drug effects, genetics)
• Comet Assay
• Fluorescent Antibody Technique
• Humans
• Lung Neoplasms (metabolism)
• Stilbenes (pharmacology)
• Telomerase (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)