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Review Open Access

Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review)

  • Authors:
    • Chaowei Zhang
    • Yuxuan Han
    • Weiyi Yao
    • Qing Hong
    • Na Chen
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Beijing Luhe Hospital, Capital Medical University, Beijing 101199, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 13
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    Published online on: November 4, 2025
       https://doi.org/10.3892/ijmm.2025.5684
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Abstract

Amino acid (AA) sensing plays an important role in maintaining cellular metabolic homeostasis as well as tumorigenesis and progression. Studies on classic AA sensing pathways such as rapamycin complex 1 (mTORC1) and general control nonderepressible 2 (GCN2) have revealed their central position in cancer metabolic reprogramming. AA sensing pathways are often hijacked in tumors to adapt to the nutrient‑deprived microenvironment, promoting cell proliferation, anti‑apoptosis and treatment tolerance. In addition, the regulation of AA sensing and transport plays a crucial role in maintaining the metabolic flexibility of tumor cells. By targeting the AA sensing mechanism, it is expected to disrupt the metabolic homeostasis of cancer cells, providing new strategies for precision therapy. The present review summarized the latest advances in the research on the role of the mTORC1 and GCN2 AA sensing pathways in tumor metabolism, emphasizing their potential and the challenges faced in cancer diagnosis and treatment. Additionally, it provided novel insights into the therapeutic targeting of AA sensing pathways and proposes future research directions aimed at overcoming current limitations in cancer metabolism therapy.
View Figures

Figure 1

Upstream regulatory mechanisms of the
mTORC1 signaling pathway. In the figure, the red lines represent
inhibitory effects, while the black lines denote promoting or
cascading responses. The portions of the study where the mechanisms
remain unclear, have been indicated them with dashed lines. Created
with MedPeer (medpeer.cn). mTORC1, rapamycin complex 1; EGF,
epidermal growth factor; EGFR, epidermal growth factor receptor;
RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma; MEK,
mitogen-activated protein kinase/extracellular signal-regulated
kinase kinase; ERK, extracellular signal-regulated kinase; RSK,
ribosomal S6 kinase; Wnt, wingless-related integration site; TNF-α,
tumor necrosis factor Alpha; IGF-1, insulin-like growth factor 1;
IRS-1, insulin receptor substrate 1; PI3K, phosphoinositide
3-kinase; PDK-1, 3-phosphoinositide-dependent protein kinase 1;
TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis
complex 2; TSC Complex, tuberous sclerosis complex; GTP, guanosine
triphosphate; Arf1, ADP-ribosylation factor 1; RAB1A, ras-related
protein aab-1A; IRS, insulin receptor substrate; S6K, S6 kinase;
LRS, leucine-rich sequence; SAR1B, secretion associated and ras
related GTPase 1B; CASTOR1, CAT1 and sestrin2 regulator 1; GATOR1,
GAP activity towards rags 1; GATOR2, GATOR1 complex 2; GDP,
guanosine diphosphate; mTOR, mechanistic target of rapamycin; SAM,
S-adenosylmethionine; SAMTOR, SAM sensor upstream of mTORC1.

Figure 2

Upstream regulatory mechanisms of the
GCN2 signaling pathway. In the figure, the yellow and green arrows
represent binding and cascade reactions, the red arrow represents
transmission, the exclamation mark indicates the state of amino
acid deficiency and the light bulb represents the activated state.
(A) The process by which GCN2 senses AA deficiency through the
binding of deacylated tRNA. (B) The process by which GCN2 interacts
with GCN1 through its RWD domain and associates with the ribosome
to achieve activation. (C) The process by which GCN2 is activated
through ribosomal translation stalling and the ribosomal P-stalk.
(D) The process of deacylated tRNA interacting with the C-terminal
domain of GCN2 to facilitate the activation of GCN2. Created with
MedPeer (medpeer.cn). GCN2, general control nonderepressible 2;
tRNA, transfer RNA.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang C, Han Y, Yao W, Hong Q and Chen N: Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review). Int J Mol Med 57: 13, 2026.
APA
Zhang, C., Han, Y., Yao, W., Hong, Q., & Chen, N. (2026). Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review). International Journal of Molecular Medicine, 57, 13. https://doi.org/10.3892/ijmm.2025.5684
MLA
Zhang, C., Han, Y., Yao, W., Hong, Q., Chen, N."Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review)". International Journal of Molecular Medicine 57.1 (2026): 13.
Chicago
Zhang, C., Han, Y., Yao, W., Hong, Q., Chen, N."Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 13. https://doi.org/10.3892/ijmm.2025.5684
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang C, Han Y, Yao W, Hong Q and Chen N: Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review). Int J Mol Med 57: 13, 2026.
APA
Zhang, C., Han, Y., Yao, W., Hong, Q., & Chen, N. (2026). Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review). International Journal of Molecular Medicine, 57, 13. https://doi.org/10.3892/ijmm.2025.5684
MLA
Zhang, C., Han, Y., Yao, W., Hong, Q., Chen, N."Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review)". International Journal of Molecular Medicine 57.1 (2026): 13.
Chicago
Zhang, C., Han, Y., Yao, W., Hong, Q., Chen, N."Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 13. https://doi.org/10.3892/ijmm.2025.5684
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