Work

AICAR induces S phase cell cycle arrest in ESCC by targeting the AMPK/mTORC1 and mTORC2/AKT pathway

Year: 2026

Type: article

Abstract: Background: 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) agonist, exhibits potent antitumor capacity across various malignancies. However, its efficacy and underlying mechanisms in esophageal squamous cell carcinoma (ESCC) remain largely unexplored. Methods: We treated HEEC, TE1, and TE13 cells with AICAR and assessed proliferation, cell cycle distribution, and expression of key signaling proteins, followed by SN38 cotreatment to evaluate apoptosis and chemosensitization. Results: AICAR treatment suppressed proliferation in all three cell lines but induced a distinct S-phase arrest specifically in ESCC cells. Mechanistically, AICAR activated AMPK, which concurrently inhibited the mTORC1 pathway via TSC2 phosphorylation and activated the mTORC2/AKT pathway through FOXO3-mediated transcriptional upregulation of Rictor. A critical difference was observed between cell types: in HEEC cells, AICAR treatment upregulated the tumor suppressor PTEN, which prevented full AKT activation. In contrast, ESCC cells, with unaltered PTEN and dysfunctional p53, sustained AKT hyperactivation. This drove cells into S-phase, where they were subsequently arrested due to the parallel inhibition of mTORC1. Furthermore, synchronizing ESCC cells in the S-phase with AICAR, followed by its withdrawal and subsequent treatment with SN38, significantly enhanced apoptosis. Conclusion: Our findings reveal that AICAR induces S-phase arrest in ESCC cells by dually modulating the mTORC1 and mTORC2/AKT signaling pathways. This differential effect, stemmed from dysfunctional p53/PTEN axis in ESCC cells, distinguishes ESCC cells from normal epithelial cells. Together, these results suggest that AICAR synchronizes ESCC cells in the S phase, thereby sensitizing them to S-phase-specific agents like SN38 and representing a potential novel strategy for ESCC treatment.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1975805