title: 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 theendogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNAdamage plays a pivotal role in maintaining genomic integrity and also acts as a molecularbarrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participatesin an integral part of proper regulation of DNA damage response (DDR). p53 is frequentlymutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavioragainst wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistantphenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathwayfollowing DNA damage, and thereby contributing to the acquisition and/or maintenance ofdrug resistance of malignant cancers. Intriguingly, we have recently found that silencing ofpro-oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53status. 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 overcometheir drug resistance. In this review, we focus on molecular mechanisms behind DDR as wellas the serious drug resistance of malignant cancers and discuss some attractive approachesto improving the outcomes of patients bearing drug-resistant cancers.
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. tozaki@chiba-cc.jp.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. mnakamura@chiba-cc.jp.
authors.forename: Mizuyo
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. oshimoza@chiba-cc.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimozato
mesh_terms: D000818:Animals; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D016159:Tumor Suppressor Protein p53
keywords: AKT; CD133; DNA damage; RUNX family; anti-cancer drug; cancer stem cell; cell cycle arrest; cell death; drug resistance; p53 family