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Peer-reviewedCC BY 4.0Frontiers in Oncology

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

  • Muping Zou1,2,3
  • Tianrui Zhang1,2,3
  • Lingbin He1,2,3
  • Jianhong Li1,2,3
  • Ze Lin1,2,3
  • Chenxi Jia1,2,3
  • Kaixuan Ma1,2,3
  • Lincui Wang1,2,3
  • Shuya Xu1,2,3
  • Bozhi Cai1,4,3
  • Libiao Wu1,4,3
  • Chunhong Ren5
3 more authors
  • Thomas Ming Swi Chang2,6
  • Pingnan Sun7,8
  • Xin Zhang1,2,3
8 affiliations
  1. 1Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College
  2. 2Shantou University Medical College
  3. 3Engineering Research Center of key technique for biotherapy of Guangdong Province
  4. 4Clinical research center, The First Affiliated Hospital of Shantou University Medical College
  5. 5International Medical Service Center, The First Affiliated hospital of Shantou University Medical College
  6. 6Artificial Cells and Organs Research Centre, Departments of Physiology, Medicine and Biomedical Engineering, Faculty of Medicine & Biomedical Sciences, McGill University
  7. 7Department of Gynecology of the First Affiliated Hospital, Shantou University Medical College
  8. 8Department of Stem Cell Research Center, Shantou University Medical College
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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.

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Cite

BibTeXRIS
BibTeX
@article{zou2026aicar,
  title = {{AICAR induces S phase cell cycle arrest in ESCC by targeting the AMPK/mTORC1 and mTORC2/AKT pathway}},
  author = {Muping Zou and Tianrui Zhang and Lingbin He and Jianhong Li and Ze Lin and Chenxi Jia and Kaixuan Ma and Lincui Wang and Shuya Xu and Bozhi Cai and Libiao Wu and Chunhong Ren and Thomas Ming Swi Chang and Pingnan Sun and Xin Zhang},
  journal = {Frontiers in Oncology},
  year = {2026},
  month = oct,
  doi = {10.3389/fonc.2026.1975805},
  url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1975805/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - AICAR induces S phase cell cycle arrest in ESCC by targeting the AMPK/mTORC1 and mTORC2/AKT pathway
AU  - Muping Zou
AU  - Tianrui Zhang
AU  - Lingbin He
AU  - Jianhong Li
AU  - Ze Lin
AU  - Chenxi Jia
AU  - Kaixuan Ma
AU  - Lincui Wang
AU  - Shuya Xu
AU  - Bozhi Cai
AU  - Libiao Wu
AU  - Chunhong Ren
AU  - Thomas Ming Swi Chang
AU  - Pingnan Sun
AU  - Xin Zhang
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Oncology
DO  - 10.3389/fonc.2026.1975805
UR  - https://www.frontiersin.org/articles/10.3389/fonc.2026.1975805/full
AB  - 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.
SN  - 2234-943X
ER  -