Unknown

Dataset Information

0

Ras puts the brake on doxorubicin-mediated cell death in p53-expressing cells.


ABSTRACT: Doxorubicin is one of the most effective molecules used in the treatment of various tumors. Contradictory reports often open windows to understand the role of p53 tumor suppressor in doxorubicin-mediated cell death. In this report, we provide evidences that doxorubicin induced more cell death in p53-negative tumor cells. Several cells, having p53 basal expression, showed increase in p53 DNA binding upon doxorubicin treatment. Doxorubicin induced cell death in p53-positive cells through expression of p53-dependent genes and activation of caspases and caspase-mediated cleavage of cellular proteins. Surprisingly, in p53-negative cells, doxorubicin-mediated cell death was more aggressive (faster and intense). Doxorubicin increased the amount of Fas ligand (FasL) by enhancing activator protein (AP) 1 DNA binding in both p53-positive and p53-negative cells, but the basal expression of Fas was higher in p53-negative cells. Anti-FasL antibody considerably protected doxorubicin-mediated cell death in both types of cells. Activation of caspases was faster in p53-negative cells upon doxorubicin treatment. In contrast, the basal expression of Ras oncoprotein was higher in p53-positive cells, which might increase the basal expression of Fas in these cells. Overexpression of Ras decreased the amount of Fas in p53-negative cells, thereby decreasing doxorubicin-mediated aggressive cell death. Overall, this study will help to understand the much studied chemotherapeutic drug, doxorubicin-mediated cell signaling cascade, that leads to cell death in p53-positive and -negative cells. High basal expression of Fas might be an important determinant in doxorubicin-mediated cell death in p53-negative cells.

SUBMITTER: Manna SK 

PROVIDER: S-EPMC3044990 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3548992 | biostudies-literature
| S-EPMC3088581 | biostudies-literature
| S-EPMC6955115 | biostudies-literature
| S-EPMC5560294 | biostudies-other
| S-EPMC2234105 | biostudies-literature
| S-EPMC4627301 | biostudies-literature
| S-EPMC5682653 | biostudies-literature
2022-04-27 | E-MTAB-8436 | biostudies-arrayexpress
| S-EPMC4260910 | biostudies-literature
| S-EPMC5693225 | biostudies-literature