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DNA Damage Response Research, Inherent and Future Nano-Based Interfaces for Personalized Medicine
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Madhu Dyavaiah, Lauren Endres, Yiching Hsieh, William Towns, Thomas J. Begley
p53 is another effector protein that has multiple roles in response to DNA damage. It activates the transcription of genes that participate in DNA repair, cell-cycle regulation, senescence, or apoptosis, depending on the type or the sources of DNA damage. Mdm2 is a negative regulator of p53 by ubiquitin-mediated proteasome degradation. Upon DNA damage, ATM, ATR, and DNA-PK can phosphorylate p53 at serine 15, while CHK1 and CHK2 can phosphorylate p53 at serine 20. Once activated, p53 can transcriptionally regulate the expression of the cyclin-dependent kinase (CDK) inhibitor p21, as well as of the proapoptotic BCL2-associated X protein (BAX) and p53 upregulated modulator of apoptosis (PUMA) proteins that induce cell-cycle arrest, senescence, or apoptosis. Moreover, p53 promotes DNA repair and deoxyribonucleoside triphosphate (dNTP) synthesis (Chen et al. 2005, Shieh et al. 1997, 2000). The preponderance of cancer-associated mutations that disrupt p53’s ability to bind DNA and activate gene transcription underscore the importance of this p53 function in mediating tumor suppression. DNA damage also induces modifications of Mdm2 leading to Mdm2 destabilization and degradation, which effectively reduce its negative regulatory effect on p53 (Wade et al. 2010). This, in combination with p53 N-terminal phosphorylation events and p53 binding to other cellular cofactors, leads to p53 stabilization and transcriptional activation.
Combination treatment with auranofin and nutlin-3a induces synergistic cytotoxicity in breast cancer cells
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Dong-Jin Ye, Yeo-Jung Kwon, Hyoung-Seok Baek, Eunah Cho, Tae-Uk Kwon, Young-Jin Chun
The synergistic effect of auranofin/nutlin-3a combination incubation on MDA-MB-231 cells was relatively weak compared to MCF-7 cells (Figure 3a). MDA-MB-231 cells are known to be triple-negative breast cancer cells due to lack of HER2, estrogen receptor (ER), and progesterone receptor (PR) expression (Chavez, Garimella, and Lipkowitz 2010). The major oncogenic feature of MDA-MB-231 is expression of mutant-type p53 (R280K) which varies from wild-type p53 expression seen in MCF-7 (Muller et al. 2009). Previously, investigators noted that unlike mutant-type p53 expressing MDA-MB-231, when function of p53 is enhanced through various pathways, cell cycle arrest and growth inhibition might be induced in wild-type p53 expressing MCF-7 (Chung et al. 2018; Li et al. 2015; Liao et al. 2016; Zhang et al. 2010). These results suggest that MCF-7 is more sensitive than MDA-MB-231 to anti-cancer strategies that utilize the tumor suppressor function of p53. In addition, the p53 mutation promotes proliferation, migration, and invasion of cells through aggressive functions (Adorno et al. 2009; Girardini et al. 2011; Muller et al. 2009). Further, R280K mutant p53 is known to exhibit loss of transactivation activity against several pro-apoptotic factors such as Bax, p53 upregulated modulator of apoptosis (PUMA), and actin-interacting protein 1 (AIP1) (Magrini et al. 2007). Clinical trial results showed similar trends with in vitro observations. Studies with patients with breast tumors carrying p53 gene mutations were found to be less sensitive to anthracyclines and/or shorter survival compare to patients with wild-type p53 expressing tumor (Aas et al. 1996; Leo et al. 2007; Miller et al. 2005; Olivier et al. 2006). Thus, it is conceivable that the p53 mutation of MDA-MB-231 attenuates the synergistic action of auranofin/nutlin-3a combination. However, further studies are needed to determine the basis for the differences in synergistic effects observed between MCF-7 and MDA-MB-231 cells.