Molecular basis for the cellular senescence program and its application to anticancer therapy.

Abstract

Although dysfunctional telomeres and oncogenic or stressful stimuli are known to trigger cellular senescence in normal human diploid cells, the molecules and signaling network involved in the cellular senescence program are not fully understood. We have been trying to identify cellular senescence-inducing factors by various means. First, we screened for an extrinsic signal that can induce cellular senescence in human lung adenocarcinoma cell line A549, and identified transforming growth factor-beta (TGF-beta) as the cellular senescence-inducing factor. Cancer cells senesced by treatment with TGF-beta impaired tumorigenicity both in vitro and in vivo, suggesting that cellular senescence functions as a tumor suppression mechanism. Next, we identified 86 independent senescence-associated genes by subtractive screening using A549-derived cell lines. Thirdly, we established novel cell lines (AST cells) from A549 cells exposed to mild oxidative stress. AST cells demonstrated functional impairment of telomerase due to perturbed subcellular localization of human telomerase reverse transcriptase, suggesting that mild oxidative stress might affect the cell fate of cancer cells. These results should provide insight into the molecular basis of the cellular senescence program.