The telomere-independent accelerated cellular senescence (ACS) has been described for tumor cells treated with chemotherapy and radiation. These DNA damage signals elicit a coordinated response that results in irreversible cell cycle arrest, characteristic senescence morphology and the expression of senescence markers. Recently, ACS has been demonstrated in tumors derived from breast cancer patients by others and from lung cancer patients by our laboratory, supporting ACS as a physiological tumor response mechanism to anti-cancer therapy. Using p53-null NCI-H1299 human non-small cell carcinoma cells undergoing ACS following exposure to topoisomerase I inhibitor camptothecin as a model, our laboratory has recently described a mechanism by which ACS cells can escape cell cycle arrest to proliferate. Rare escaped cells appear to have bypassed the senescence program by deregulating the expression of the cyclin dependent kinase Cdc2/Cdk1 such that specific inhibition of the Cdc2/Cdk1 kinase both cause escaped cells to re-arrest and block the escape of ACS cells. We hypothesize that ACS accounts for observed human lung cancer response to chemotherapy and escape from ACS represents a mechanism of tumor recurrence or progression. To examine essential aspects of this hypothesis and to further define the mechanism by which cancer cells undergo ACS and escape, the project proposes to further examine the role of Cdc2/Cdk1, cyclin B1 and cyclin-dependent kinase inhibitors p21 and p27 in both ACS and escape. Additionally, in the study we also propose to conduct a clinicopathologic study on 40 patients with high risk non-small cell lung cancer given neoadjuvant chemo- radiotherapy, who will be enrolled in an ongoing Postitron Emission Tomography study. These studies should yield the clinical relevance, novel markers and new mechanistic insights of accelerated cellular senescence in human cancers.
| Wang, Qin; Wu, Peter C; Dong, David Z et al. (2013) Polyploidy road to therapy-induced cellular senescence and escape. Int J Cancer 132:1505-15 |
| Wang, Qin; Wu, Peter C; Roberson, Rachel S et al. (2011) Survivin and escaping in therapy-induced cellular senescence. Int J Cancer 128:1546-58 |
| Wu, P C; Wang, Q; Dong, Z M et al. (2010) Expression of coxsackie and adenovirus receptor distinguishes transitional cancer states in therapy-induced cellular senescence. Cell Death Dis 1:e70 |
