ROS-mediated genotoxic stress is involved in NaAsO2-induced cell cycle arrest, stemness enhancement and chemoresistance of prostate cancer cells in a p53-independent manner.

Abstract

Several epidemiological studies reported that chronic arsenic exposure increased risk of prostate cancer. This study aimed to investigate whether chronic NaAsO2 exposure elevates stemness and chemoresistance in prostate cancer cells. DU145 (wild-type p53) and PC-3 (p53-null) cells were exposed to NaAsO2 (2 μmol/L) for 30 generations. IC50s to docetaxel and cisplatin were increased in NaAsO2-exposed DU145 and PC-3 cells. The number of tumor spheres was elevated in NaAsO2-exposed DU145 and PC-3 cells. Nanog, SOX-2 and ALDH1A1, three markers of cancer stemness, were upregulated in NaAsO2-exposed PC-3 spheres. Moreover, NaAsO2-exposed DU145 and PC-3 cells were arrested in G2/M phase. Histone H2AX phosphorylation on Ser139, an indicator for DNA double-strand break, was upregulated in NaAsO2-exposed DU145 and PC-3 cells. ATM phosphorylation on Ser1981, a key sensor of genotoxic stress, was rapidly elevated in NaAsO2-exposed DU145 cells. Phosphor-p53, a downstream molecule of ATM signaling, and p21, a direct target of p53, were upregulated in NaAsO2-exposed DU145 cells. Unexpectedly, p21 was also elevated in NaAsO2-exposed p53-null PC-3 cells. Antioxidant NAC alleviated NaAsO2-induced ATM phosphorylation, cell cycle arrest, and subsequent stemness enhancement and chemoresistance in both DU145 and PC-3 cells. These results suggest that ROS-mediated genotoxic stress is involved in NaAsO2-induced cell cycle arrest, stemness enhancement and chemoresistance of prostate cancer cells in a p53-independent manner.

• Authors: Zhi-Hui Zhang, Qian Hong, Zhi-Cheng Zhang, Wei-Yang Xing, Shen Xu, Qi-Xing Tian, Qing-Lin Ye, Hua Wang, De-Xin Yu, Dong-Dong Xie, De-Xiang Xu
• Journal: Ecotoxicology and environmental safety (Ecotoxicol Environ Saf) Vol. 208 Pg. 111436 (Jan 15 2021) ISSN: 1090-2414 [Electronic] Netherlands
• PMID: 33039867 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Arsenates
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• sodium arsenate

Topics

• Apoptosis
• Arsenates (toxicity)
• Cell Cycle
• Cell Cycle Checkpoints (physiology)
• Cell Line, Tumor
• DNA Damage (physiology)
• Drug Resistance, Neoplasm (physiology)
• Humans
• Male
• Phosphorylation
• Prostatic Neoplasms (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics)