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Published on: February 9, 2024
Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma
Yu-Han Shen1, Bo-Rong Chen, Shur-Hueih Cherng
1Institute of Biomedical Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan.
Abstract:
DNA-damaging agents are commonly used as anticancer therapeutics. Unfortunately, such drugs induced DNA damages as well as DNA repair are important in mediating drug resistance to cancer treatments. To evaluate changes in DNA repair proteins that occur in DNA damage agent treatment, we challenged human A549 lung adenocarcinoma cells with cisplatin. hHR23/RAD23, an accessory protein involved in nucleotide-excision repair (NER) at an early lesion-recognition step, was upregulated by cisplatin in a dose- and time-dependent manner. Upregulation of hHR23 expression by low-dose cisplatin was accompanied by an increase in p53, p21, and XPC protein levels. Importantly, knockdown of hHR23B by RNA interference decreased DNA repair activity, cell survival, and induction of p53 and XPC following treatment with cisplatin. Conversely, overexpression of hHR23B enhanced repair activity towards cisplatin-damaged DNA. Inhibition of MEK/ERK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways attenuated cisplatin-induced hHR23 expression, indicating that these pathways are involved in the process. The increase in hHR23 protein expression mediated by MEK/ERK signaling was due to increased translational efficiency resulting from phosphorylation/activation of the translation-initiating factor eIF-4B. Taken together, these results suggest that cisplatin-induced increases in hHR23 levels are regulated by proliferative signaling pathways and important for DNA repair.
Insights
Cisplatin anticancer drug resistance involves DNA repair. Upregulation of hHR23/RAD23 protein by cisplatin enhances DNA repair activity and cell survival, suggesting a role in cancer treatment efficacy.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- DNA-damaging agents are crucial anticancer therapeutics.
- Drug resistance in cancer is mediated by DNA damage and repair mechanisms.
- Understanding DNA repair protein regulation is key to improving cancer treatment.
Purpose of the Study:
- To investigate the role of DNA repair proteins in response to cisplatin treatment.
- To elucidate the regulation of hHR23/RAD23 protein expression and its impact on DNA repair and cell survival.
Main Methods:
- Human A549 lung adenocarcinoma cells were treated with cisplatin.
- Changes in DNA repair protein levels (hHR23/RAD23, p53, p21, XPC) were analyzed.
- RNA interference was used to knock down hHR23B expression.
- Signaling pathways (MEK/ERK, PI3K/AKT) were inhibited to study their role.
Main Results:
- Cisplatin upregulated hHR23/RAD23 in a dose- and time-dependent manner.
- Knockdown of hHR23B reduced DNA repair, cell survival, and p53/XPC induction.
- Overexpression of hHR23B enhanced repair of cisplatin-damaged DNA.
- MEK/ERK and PI3K/AKT pathways were involved in cisplatin-induced hHR23 expression.
- MEK/ERK signaling increased hHR23 translation via eIF-4B activation.
Conclusions:
- Cisplatin-induced hHR23/RAD23 upregulation is regulated by proliferative signaling pathways.
- Increased hHR23 levels are critical for DNA repair and may influence cancer treatment outcomes.
- Targeting hHR23/RAD23 could be a strategy to overcome cisplatin resistance.
