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Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review)

  • Authors:
    • Amer Alasadi
    • Noor Fadhil
    • Sean Chen
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA, Department of Nutrition Science, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
    Copyright: © Alasadi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 103
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    Published online on: September 4, 2025
       https://doi.org/10.3892/wasj.2025.391
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Abstract

AMP‑activated protein kinase (AMPK) and mechanistic target of rapamycin complexes (mTORCs; mTORC1 and mTORC2) have critical functions in controlling tumor cell metabolism, reciprocally affecting the anabolic and catabolic pathways that control cell growth, proliferation and survival. AMPK serves as a key energy sensor, activated in response to low cellular energy levels, while the action of mTORCs becomes evident under conditions with high nutrient and growth factors. The dysregulation of these cascades is notably detected in a number of types of cancer, where reduced AMPK activity and unrestrained mTOR signaling pathways accelerate metabolic shifts that support carcinogenesis. The connection between AMPK and mTOR is significant. AMPK plays a role in hindering mTOR signaling, thus diminishing protein biosynthesis and stimulating autophagy. This strengthens cellular homeostasis, progression and survival during severe metabolic distress. Nevertheless, the function of AMPK in tumors is multifaceted. At the same time, it commonly functions as a tumor suppressor; evidence suggests that in specific environments, AMPK may stimulate tumor development by supporting the survival of tumor cells under adverse conditions, such as metabolic deprivation. This dualism highlights that the therapeutic targeting of AMPK/mTOR signaling pathways needs to be addressed carefully, as the consequences may vary, depending on the specific cancer microenvironment and nutrient state. The present review summarizes evidence from the literature in an aim to shed light onto the complex balance of the actions, regulation and critical role of AMPK and mTORCs in cancer cell metabolism. The present review aimed to provide insight that may lead to the development of novel targeted therapies that diminish the threat of unfavorable consequences associated with modified metabolic control.
View Figures

Figure 1

The mTOR pathway is organized as two
unique mTOR complexes, termed mTORC1 and mTORC2. mTORC1 is a
protein complex of mTOR, Raptor, Deptor, mLST8 and PRAS40. mTORC1
phosphorylates downstream targets to control protein and lipid
biosynthesis, lysosomal biogenesis, autophagy, glucose metabolism,
and nucleotide synthesis. mTORC2 is a protein complex of mTOR,
Debtor, Raptor, mLST8, mSIN1, and Protor. mTORC2 regulates cell
proliferation, survival, cytoskeleton and cell migration. mTOR,
mammalian target of rapamycin; mTORC, mammalian target of rapamycin
complex.

Figure 2

With sufficient nutrients and growth
factors, mTORCs stimulate cancer cell growth, propagation and
survival. mTORC1 and mTORC2 control the metabolic sources for
protein biosynthesis through translation and amino acid transport
and glutamine metabolism, respectively. Both complexes are
participated in metabolism of glucose via glycolysis and hexosamine
synthesis. Mitochondrial metabolism is controlled by mTORC1 and
mTORC2 by regulating biogenesis, ATP synthesis, cell survival, and
cytoskeleton organization. mTORCs modulate lipid metabolism by
promoting lipogenesis, adipogenesis, and phospholipid synthesis.
mTORC1 and mTORC2 significantly regulate the synthesis of purine,
pyrimidine and PPP, essential biomolecules for cancer cell
proliferation and survival. AA, amino acid; PL, phospholipid
synthesis; mTOR, mammalian target of rapamycin; mTORC, mammalian
target of rapamycin complex; PPP, pentose phosphate pathway.

Figure 3

Combination therapy strategy. Under
energy stress, AMPK is activated, inhibiting mTORC1 through direct
and indirect inhibition by TSC1/2 activation and activating mTORC2.
AMPK inhibits the anabolic pathways that are under mTORC1
activation. AMPK activators and mTORC1/2 inhibitors stimulate the
catabolic pathways and reduce the cell growth, survival, and
propagation of cancer cells. mTOR, mammalian target of rapamycin;
mTORC, mammalian target of rapamycin complex; AMPK, AMP-activated
protein kinase; TSC1/2, tuberous sclerosis protein 1/2.
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Spandidos Publications style
Alasadi A, Fadhil N and Chen S: Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review). World Acad Sci J 7: 103, 2025.
APA
Alasadi, A., Fadhil, N., & Chen, S. (2025). Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review). World Academy of Sciences Journal, 7, 103. https://doi.org/10.3892/wasj.2025.391
MLA
Alasadi, A., Fadhil, N., Chen, S."Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review)". World Academy of Sciences Journal 7.6 (2025): 103.
Chicago
Alasadi, A., Fadhil, N., Chen, S."Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review)". World Academy of Sciences Journal 7, no. 6 (2025): 103. https://doi.org/10.3892/wasj.2025.391
Copy and paste a formatted citation
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Spandidos Publications style
Alasadi A, Fadhil N and Chen S: Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review). World Acad Sci J 7: 103, 2025.
APA
Alasadi, A., Fadhil, N., & Chen, S. (2025). Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review). World Academy of Sciences Journal, 7, 103. https://doi.org/10.3892/wasj.2025.391
MLA
Alasadi, A., Fadhil, N., Chen, S."Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review)". World Academy of Sciences Journal 7.6 (2025): 103.
Chicago
Alasadi, A., Fadhil, N., Chen, S."Deciphering the critical roles of the AMPK/mTOR signaling pathway in cancer cell metabolism (Review)". World Academy of Sciences Journal 7, no. 6 (2025): 103. https://doi.org/10.3892/wasj.2025.391
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