Estrogen-mediated inhibition of purine metabolism and cell cycle arrest as a novel therapeutic approach in colorectal cancer

• Published in: Molecular and cellular endocrinology 2025-01, Vol.596, p.112414, Article 112414
• Main Authors: Zamer, Batoul Abi, Shafarin, Jasmin, Sharaf, BasmaM, Hroub, HamzaM. Al, Soares, Nelson C., Semreen, Mohammad H., Hamad, Mawieh, Muhammad, Jibran Sualeh
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Proliferation - drug effects; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA Damage; Estradiol - pharmacology; Estrogen; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; Estrogens - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; Humans; Metabolomics; Purine metabolism; Purines - pharmacology; Signal Transduction - drug effects; Transcriptomics
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2024.112414

Purine metabolism is upregulated in various cancers including colorectal cancer (CRC). While previous work has elucidated the role of estrogen (E2) in metabolic reprogramming and ATP production, the effect of E2 on purine metabolism remains largely unknown. Herein, the impact of E2 signalling on purine metabolism in CRC cells was investigated using metabolome and transcriptome profiling of cell extracts derived from E2-treated HCT-116 cells with intact or silenced estrogen receptor alpha (ERα). Purine metabolic pathway enrichment analysis showed that 27 genes in the de novo purine synthesis pathway were downregulated in E2-treated CRC cells. Downstream consequences of E2 treatment including the induction of DNA damage, cell cycle arrest, and apoptosis were all shown to be ERα-dependent. These findings demonstrate, for the first time, that E2 exerts a significant anti-growth and survival effect in CRC cells by targeting the purine synthesis pathway in a ERα-dependent manner, meriting further investigation of the therapeutic utility of E2 signalling in CRC. •E2 downregulates 27 genes in CRC purine synthesis via ERα.•E2-induced DNA damage is ERα-dependent in CRC cells.•E2 causes cell cycle arrest in CRC cells through ERα.•Apoptosis in CRC cells is triggered by E2 via ERα.•E2 inhibits CRC cell growth by targeting purine metabolism.