p38 MAPK and JNK Antagonistically Control Senescence and Cytoplasmic p16INK4A Expression in Doxorubicin-Treated Endothelial Progenitor Cells

Abstract

Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs) exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16 INK4A localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16INK4A, suggests that doxorubicin-induced p16 INK4A does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16 INK4A expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicin-treated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity.

Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus

“…Although nuclear expression of CDKN2A is usually associated to cell-cycle control, cytoplasmic accumulation has also been associated to senescent phenotype induced by stress. 68 Histological studies suggest that non-ciliated secretory cells give rise to ciliated cells and function as a long-term self-renewing stem cell population in the intrapulmonary airways. 59 In addition, it has been reported that the adult mouse lung contains a minor population of multipotent epithelial stem cells with the capacity of self-renewal and to give rise to all epithelial progenitors that reside in discrete microenviromental niches along the proximal-distal axis.…”

Sublethal heat shock induces premature senescence rather than apoptosis in human mesenchymal stem cells

“…Emerging evidence suggests that SIPS rather than apoptosis is a predominant response of human adult cells challenged with various stressors: hydrogen peroxide (Orciani et al 2010;Brandl et al 2011a, b), ionizing radiation (Suzuki and Boothman 2008), gamma radiation (Cmielova et al 2012), doxorubicin (Spallarossa et al 2010), and tumor necrosis factor alpha (Zhang et al 2009). It was generally accepted that SIPS is an important tumor suppression mechanism preventing the proliferation of cells that are at risk of malignant transformation.…”

Pharmacologic Inhibition of Cardiac Stem Cell Senescence

“…Importantly, it has been shown that p38MAPK inhibition can maintain hematopoietic stem cell quiescence, inhibiting the exhaustion of the hematopoietic stem cell pool (Ito, et al, 2006). In addition, p38MAPK inhibition can reduce cellular senescence in EPC exposed to doxorubicin (Spallarossa, et al, 2010). No data are available regarding hCSC.…”