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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-? 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.

SUBMITTER: Chen RJ

PROVIDER: S-EPMC5596539 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Chen Rong-Jane RJ Wu Pei-Hsuan PH Ho Chi-Tang CT Way Tzong-Der TD Pan Min-Hsiung MH Chen Hsiu-Min HM Ho Yuan-Soon YS Wang Ying-Jan YJ

Cell death & disease 20170810 8

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; ho ...[more]

PMID: 28796247

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Project description:Cyclin Dependent Kinase-2 Associated Protein-1 (CDK2AP1) is known to be a tumor suppressor that plays a role in cell cycle regulation by sequestering monomeric CDK2, and targeting it for proteolysis. A reduction of CDK2AP1 expression is considered to be a negative prognostic indicator in patients with oral squamous cell carcinoma and also associated with increased invasion in human gastric cancer tissue. CDK2AP1 overexpression was shown to inhibit growth, reduce invasion and increase apoptosis in prostate cancer cell lines. In this study, we investigated the effect of CDK2AP1 downregulation in primary human dermal fibroblasts. Using a short-hairpin RNA to reduce its expression, we found that knockdown of CDK2AP1 in primary human fibroblasts resulted in reduced proliferation and in the induction of senescence associated beta-galactosidase activity. CDK2AP1 knockdown also resulted in a significant reduction in the percentage of cells in the S phase and an accumulation of cells in the G1 phase of the cell cycle. Immunocytochemical analysis also revealed that the CDK2AP1 knockdown significantly increased the percentage of cells that exhibited ?-H2AX foci, which could indicate presence of DNA damage. CDK2AP1 knockdown also resulted in increased mRNA levels of p53, p21, BAX and PUMA and p53 protein levels. In primary human fibroblasts in which p53 and CDK2AP1 were simultaneously downregulated, there was: (a) no increase in senescence associated beta-galactosidase activity, (b) decrease in the number of cells in the G1-phase and increase in number of cells in the S-phase of the cell cycle, and (c) decrease in the mRNA levels of p21, BAX and PUMA when compared with CDK2AP1 knockdown only fibroblasts. Taken together, this suggests that the observed phenotype is p53 dependent. We also observed a prominent increase in the levels of ARF protein in the CDK2AP1 knockdown cells, which suggests a possible role of ARF in p53 stabilization following CDK2AP1 knockdown. Altogether, our results show that knockdown of CDK2AP1 in primary human fibroblasts reduced proliferation and induced premature senescence, with the observed phenotype being p53 dependent.

Dataset Information

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

Publications

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

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