Overexpression of the p21sdi1 gene induces senescence-like state in human cancer cells:: implication for senescence-directed molecular therapy for cancer

被引:37
作者
Kagawa, S
Fujiwara, T
Kadowaki, Y
Fukazawa, T
Sok-Joo, R
Roth, JA
Tanaka, N
机构
[1] Okayama Univ, Sch Med, Dept Surg 1, Sect Mol Oncol, Okayama 7008558, Japan
[2] Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Sect Thorac Mol Oncol, Houston, TX 77030 USA
关键词
p21; senescence; adenovirus vector; human cancer;
D O I
10.1038/sj.cdd.4400549
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Normal cells in a culture enter a nondividing state after a finite number of population doubling, which is termed replicative senescence, whereas cancer cells have unlimited proliferative potential and are thought to exhibit an immortal phenotype by escaping from senescence. The p21 gene (also known as sdi1), which encodes the cyclin-dependent kinase inhibitor, is expressed at high levels in senescent cells and contributes to the growth arrest. To examine if the p21(sdi1) gene transfer could induce senescence in human cancer cells, we utilized an adenoviral vector-based expression system and four human cancer cell lines differing in their p53 status. Transient overexpression of p21(sdi1) on cancer cells induced quiescence by arresting the cell cycle at the G(1) phase and exhibited morphological changes, such as enlarged nuclei as well as a flattened cellular shape, specific to the senescence phenotype. We also showed that p21(sid1)-transduced cancer cells expressed beta-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Moreover, the polymerase chain reaction-based assay demonstrated that levels of telomerase activity were significantly lower in p21(sdi1)-expressing cells compared to parental cancer cells. These observations provide the evidence that p21(sdi1) overexpression could induce a senescence-like state and reduce telomerase activity in human cancer cells, suggesting that these novel p21(sdi1) functions may have important implications for anticancer therapy.
引用
收藏
页码:765 / 772
页数:8
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