Novel implications of DNA damage response in drug resistance of malignant cancers obtained from the functional interaction between p53 family and RUNX2

Abstract

During the lifespan of cells, their genomic DNA is continuously exposed to the endogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNA damage plays a pivotal role in maintaining genomic integrity and also acts as a molecular barrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participates in an integral part of proper regulation of DNA damage response (DDR). p53 is frequently mutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavior against wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistant phenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathway following DNA damage, and thereby contributing to the acquisition and/or maintenance of drug resistance of malignant cancers. Intriguingly, we have recently found that silencing of\ pro-oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53 status. Meanwhile, cancer stem cells (CSCs) have stem cell properties such as drug resistance. Therefore, the precise understanding of the biology of CSCs is quite important to overcome their drug resistance. In this review, we focus on molecular mechanisms behind DDR as wel as the serious drug resistance of malignant cancers and discuss some attractive approaches to improving the outcomes of patients bearing drug-resistant cancers.