Polyploidy road to therapy‐induced cellular senescence and escape

• Published in: International journal of cancer 2013-04, Vol.132 (7), p.1505-1515
• Main Authors: Wang, Qin, Wu, Peter C., Dong, David Z., Ivanova, Iana, Chu, Elizabeth, Zeliadt, Steven, Vesselle, Hubert, Wu, Daniel Y.
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cancer; cancer therapeutics; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; CDC2 Protein Kinase - metabolism; Cdc2/Cdk1; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Proliferation - drug effects; cellular senescence; Cellular Senescence - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclin-dependent kinases; Humans; Immunoprecipitation; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Medical research; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoadjuvant Therapy - adverse effects; Neoplasm Staging; Polyploidy; Prognosis; RNA, Small Interfering - genetics; Survival Rate; Tumor Cells, Cultured; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27810

Therapy‐induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non‐small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin‐dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics. What's new? Ideally, treating cancer means killing the diseased cells. But for those cells that won't curl up and die, making them stop dividing will suffice. Getting the cells to enter senescence halts the cell cycle ‐‐ but the condition is, unfortunately, reversible. Deregulated Cdk1 expression seems to help cells escape cell cycle arrest. This study of patients with advanced lung cancer shows that aberrant expression of Cdk1 promotes polyploidy and enables senescent cells to re‐enter the cell cycle. The presence of therapy‐induced senescent cells, they found, was a bad sign that the disease was likely to recur.