Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM–Chk1/2–Cdc25C pathway

Journal Article · Thu Jan 15 04:00:00 EST 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2014.11.003· OSTI ID:22465685

Ma, Yong-Cheng ^[1]; Su, Nan ^[2]; Shi, Xiao-Jing; Zhao, Wen; Ke, Yu ^[3]; Zi, Xiaolin ^[4]; Zhao, Ning-Min; Qin, Yu-Hua; Zhao, Hong-Wei ^[1]; Liu, Hong-Min ^[3]

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1. Clinical Pharmacology Laboratory, Henan Province People's Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan (China)
2. Department of Quality Detection and Management, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan (China)
3. School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan (China)
4. Department of Urology, University of California, Irvine, Orange, CA (United States)

Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM–Chk1/2–Cdc25C pathway. - Highlights: • Jaridonin induced G2/M phase arrest through induction of redox imbalance. • Jaridonin increased the level of ROS through depleting glutathione in cell. • ATM–Chk1/2–Cdc25C were involved in Jaridonin-induced cell cycle arrest. • Jaridonin selectively inhibited cancer cell viability and cell cycle progression.

• OSTI ID: 22465685
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 282; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL CYCLE
CELL DIVISION
CYSTEINE
DNA DAMAGES
ESOPHAGUS
GLUTATHIONE
HUMAN POPULATIONS
NEOPLASMS
OXYGEN
PHOSPHORYLATION
VIABILITY