Exercise and Regulation of PI3K/Akt/mTOR and AMPK Pathways in Cancer: Molecular Mechanisms and Therapeutic Implications: A Narrative Review

Overview: Dysregulation of the PI3K/Akt/mTOR and AMPK pathways is central to cancer development, driving uncontrolled cell growth, metabolic disturbances, and resistance to cell death and therapy. Exercise has emerged as an effective non-drug strategy that can modify these pathways and influence tumor-related cellular processes. Methods: This review compiles evidence from 2015 to 2025 on how exercise impacts PI3K/Akt/mTOR and AMPK signaling in cancer. Results: Findings show that exercise activates AMPK, an energy sensor that boosts glucose uptake, insulin sensitivity, autophagy, and mitochondrial biogenesis. Through AMPK activation, exercise reduces anabolic signaling and excessive protein synthesis, which often promotes tumor growth, while supporting healthier metabolism. At the same time, exercise inhibits the PI3K/Akt/mTOR pathway, reducing cell proliferation, affecting growth factors like insulin and IGF-1, and restoring metabolic balance across tissues. These combined effects improve cellular stability, lessen tumor-promoting mechanisms, and may enhance responsiveness to cancer treatments, making exercise a valuable complement for cancer prevention and therapy. Most current insights come from preclinical studies or epidemiological data, with few clinical trials examining exercise-induced molecular changes in human tumors. Conclusion: More research is needed to identify optimal exercise regimens, understand pathway-specific effects, and evaluate their clinical relevance to better incorporate exercise into personalized cancer care.

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