Ionizing radiation-induced responses in human cells with differing TP53 status.
Ionizing radiation triggers diverse responses in human cells encompassing apoptosis, necrosis, stress-induced premature senescence (SIPS), autophagy, and endopolyploidy (e.g., multinucleation). Most of these responses result in loss of colony-forming ability in the clonogenic survival assay. However, not all modes of so-called clonogenic cell "death" are necessarily advantageous for therapeutic outcome in cancer radiotherapy. For example, the crosstalk between SIPS and autophagy is considered to influence the capacity of the tumor cells to maintain a prolonged state of growth inhibition that unfortunately can be succeeded by tumor regrowth and disease recurrence. Likewise, endopolyploid giant cells are able to segregate into near diploid descendants that continue mitotic activities. Herein we review the current knowledge on the roles that the p53 and p21(WAF1) tumor suppressors play in determining the fate of human fibroblasts (normal and Li-Fraumeni syndrome) and solid tumor-derived cells after exposure to ionizing radiation. In addition, we discuss the important role of WIP1, a p53-regulated oncogene, in the temporal regulation of the DNA damage response and its contribution to p53 dynamics post-irradiation. This article highlights the complexity of the DNA damage response and provides an impetus for rethinking the nature of cancer cell resistance to therapeutic agents.
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada. razmik.mirzayans@albertahealthservices.ca.
Razmik
R
Mirzayans
Bonnie
B
Andrais
April
A
Scott
Ying W
YW
Wang
David
D
Murray
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects*; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D011123:Polyploidy; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53