Resistance of Quiescent Human Diploid Fibroblasts to High Dose of External Oxidative Stress and Induction of Senescence
Danijela Domazet-Damjanov, Mallika Somayajulu-Nitu, Siyaram Pandey*
Identifiers and Pagination:Year: 2009
First Page: 149
Last Page: 160
Publisher Id: TOBIOJ-2-149
Article History:Received Date: 16/03/2009
Revision Received Date: 09/06/2009
Acceptance Date: 12/06/2009
Electronic publication date: 02/12/2009
Collection year: 2009
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In response to external oxidative stress/DNA damaging agents, mammalian cells may choose one of the following pathways to avoid propagation of the damaged cells: repair the DNA and proceed with the normal cell cycle; trigger apoptosis; or undergo senescence to block cell division. If these safeguard mechanisms fail, cells containing damaged/mutated DNA will continue to propagate leading to cancer. Working with Human Diploid Fibroblasts, we have observed that young quiescent fibroblasts, unlike dividing fibroblasts, do not undergo apoptosis when subjected to high dose of external oxidative stress. Interestingly, when those quiescent fibroblasts are sub-cultured following H2O2 treatment, they display all the features of the senescent cell phenotype. Our results have indicated that p21 and MnSOD over-expression in quiescent cells is highly correlated to resistance to oxidative stress and may induce senescence. Moreover, there was no observable DNA damage in quiescent fibroblasts after 500 μM H2O2 treatment even though oxidative damage to lipids and proteins was detected both before and after treatment. Most importantly, the mitochondrial membrane potential in quiescent cells remained unchanged even after exposure to a high dose of external oxidative stress. In dividing cells, Bcl-2 expression was down-regulated whereas Bax expression was up-regulated following oxidative stress. On the other hand, Bcl-2 levels remained high and Bax was down-regulated in quiescent cells under identical treatment. Our results reveal that the over-expression of p21 and Mn-SOD and the down-regulation of Bax in quiescent cells could be responsible for their resistance against external oxidative stress and onset of senescence.