Changes in the Proteome Profile of A549 Cells Following Helichrysetin-Induced Apoptosis Suggest the Involvement of DNA Damage Response and Cell Cycle Arrest-Associated Proteins.

Abstract

Our previous findings demonstrated that Helichrysetin possessed promising anti-cancer activity. It was able to induce apoptosis in the A549 cell line. However, its mechanism of action is unknown. The present study aimed to unravel possible underlying molecular mechanisms of helichrysetin-induced apoptosis in A549 (human lung carcinoma) cells using comparative quantitative proteomics (iTRAQ labeled), followed by an exhaustive bioinformatics analysis. Our results suggested that DNA damage response (DDR) and cell cycle arrest were responsible for lung cancer cell death with helichrysetin treatment. Among proteins that changed in abundance were Nrf2 and HMOX1. They are oxidative stress-related proteins and were increased in abundance. BRAT1 was also increased in abundance, suggesting an increase in DNA damage repair, indicating the occurrence of DNA damage due to oxidative stress. However, several essential DDR downstream proteins such as p-ATM, BRCA1, FANCD2, and Rb1 that would further increase DNA damage were found to be dramatically decreased in relative abundance. Cell cycle-related proteins, p53, p21, and cyclin D1, were increased while cyclin A, cyclin E, and cdk2 were decreased. This is predicted to facilitate S-phase arrest. Furthermore, excessive DNA damage and prolonged arrest would in turn result in the induction of mitochondrial-mediated apoptosis. Based on these observations, we postulate that the effects of helichrysetin were in part via the suppression of DNA damage response which led to DNA damage and prolonged cell cycle arrest. Subsequently, this event initiated mitochondrial-mediated apoptosis in A549 lung cancer cells.

• Authors: Yen Fong Ho, Noor Liana Mat Yajit, Jeng-Yuan Shiau, Sri Nurestri Abd Malek, Lie-Fen Shyur, Saiful Anuar Karsani
• Journal: Applied biochemistry and biotechnology (Appl Biochem Biotechnol) Vol. 195 Issue 11 Pg. 6867-6880 (Nov 2023) ISSN: 1559-0291 [Electronic] United States
• PMID: 36947367 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Cell Cycle Proteins
• Proteome
• helichrysetin
• BRAT1 protein, human
• Nuclear Proteins

Topics

• Humans
• Cell Cycle Proteins (metabolism)
• A549 Cells
• Proteome (pharmacology)
• Cell Line, Tumor
• Cell Cycle Checkpoints
• Apoptosis
• Lung Neoplasms (drug therapy, genetics, metabolism)
• DNA Damage
• Cell Cycle
• Nuclear Proteins (pharmacology)