If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells.
Inhibition of the program of apoptosis has been reported to have little or no effect on clonogenic survival after treatment with drugs or radiation in several tumor cell lines. A decrease in apoptosis is compensated in such cell lines by an increase in the fractions of cells that undergo permanent growth arrest with phenotypic features of cell senescence, or die through the process of mitotic catastrophe. Most of the tested tumor cell lines have retained the capacity of normal cells to undergo accelerated senescence after treatment with DNA-interactive drugs, ionizing radiation, or cytostatic agents. p53 and p21(Waf1/Cip1/Sdi1) act as positive regulators of treatment-induced senescence, but they are not required for this response in tumor cells. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may produce secreted proteins with potential tumor-promoting activities. The expression of such proteins is mediated at least in part by the induction of p21(Waf1/Cip1/Sdi1). The other anti-proliferative response of tumor cells is mitotic catastrophe, a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Mitotic catastrophe is induced by different classes of cytotoxic agents, but the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. Mitotic catastrophe can also develop as a consequence of aberrant reentry of tumor cells into cell cycle after prolonged growth arrest. Elucidation of the factors that regulate different aspects of treatment-induced senescence and mitotic catastrophe should assist in improving the efficacy and decreasing side effects of cancer therapy.
Roninson
I B
IB
Department of Molecular Genetics, University of Illinois at Chicago, Chicago 60607-7170, USA. roninson@uic.edu
Broude
E V
EV
Chang
B D
BD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006131:Growth Inhibitors / Q000633:toxicity*; D006801:Humans; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors