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<p>Resveratrol (Res), a natural polyphenolic compound, exhibits multiple antitumor activities against acute myeloid leukemia (AML), though its mechanisms remain incompletely understood. In this study, CCK-8 assay, CFSE flow cytometry, Transwell assays, and flow cytometry assessed proliferation, invasion, migration, and programmed cell death in MV4-11 and MOLM-13 leukemic cell lines. Western blotting examined cell death regulatory factors (Cleaved-caspase 3/caspase 3, Bax, Bcl-2), aerobic glycolysis proteins (GLUT1, HK2, LDHA, PKM2), cuproptosis-related proteins (FDX1, DLAT, Lip-DLAT, DLST, Lip-DLST, HSP70, SDHB), and PI3K/AKT pathway proteins (p-PI3K/PI3K, p-AKT/AKT). Intracellular Cu<sup>2</sup>⁺ levels were measured colorimetrically, while glucose uptake, lactate, and ATP levels were quantified to evaluate cellular metabolism. Mechanistic investigations utilized PFKFB3 overexpression, PI3K activator (740 Y-P), and inhibitor (LY294002) intervention experiments. The antitumor efficacy of Res was validated in an AML xenograft mouse model. Res significantly inhibited AML cell proliferation, invasion, and migration while promoting apoptosis. It markedly downregulated FDX1, Lip-DLAT, Lip-DLST, and SDHB while upregulating HSP70 and intracellular Cu<sup>2</sup>⁺, inducing cuproptosis—an effect reversible by the cuproptosis inhibitor TTM. Res reduced glucose uptake, lactate production, ATP generation, and downregulated GLUT1, HK2, LDHA, and PKM2, thereby suppressing aerobic glycolysis-a process reversed by PFKFB3 overexpression. Furthermore, Res inhibited PI3K and AKT phosphorylation; the PI3K activator 740 Y-P counteracted Res-mediated effects while the PI3K inhibitor LY294002 enhanced them. In vivo experiments confirmed that Res treatment markedly diminished tumor size and mass, lowered Ki-67 proliferation marker, enhanced programmed cell death, suppressed PI3K/AKT signaling, decreased glycolytic enzyme levels, and elevated copper-dependent cell death mediators. Res exerts anti-AML effects by inhibiting the PI3K/AKT pathway while coordinately regulating aerobic glycolysis and cuproptosis in AML cells.</p> Graphical Abstract <p>Resveratrol effectively suppresses tumor progression by inhibiting the PI3K/AKT axis, downregulating aerobic glycolysis, and promoting cuproptosis.</p> <p></p>

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Resveratrol inhibits aerobic glycolysis and promotes cuproptosis in acute myeloid leukemia via the PI3K/AKT signaling pathway

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Cheng Lian,
  • Yanhui Liu,
  • Pingchong Lei

摘要

Resveratrol (Res), a natural polyphenolic compound, exhibits multiple antitumor activities against acute myeloid leukemia (AML), though its mechanisms remain incompletely understood. In this study, CCK-8 assay, CFSE flow cytometry, Transwell assays, and flow cytometry assessed proliferation, invasion, migration, and programmed cell death in MV4-11 and MOLM-13 leukemic cell lines. Western blotting examined cell death regulatory factors (Cleaved-caspase 3/caspase 3, Bax, Bcl-2), aerobic glycolysis proteins (GLUT1, HK2, LDHA, PKM2), cuproptosis-related proteins (FDX1, DLAT, Lip-DLAT, DLST, Lip-DLST, HSP70, SDHB), and PI3K/AKT pathway proteins (p-PI3K/PI3K, p-AKT/AKT). Intracellular Cu2⁺ levels were measured colorimetrically, while glucose uptake, lactate, and ATP levels were quantified to evaluate cellular metabolism. Mechanistic investigations utilized PFKFB3 overexpression, PI3K activator (740 Y-P), and inhibitor (LY294002) intervention experiments. The antitumor efficacy of Res was validated in an AML xenograft mouse model. Res significantly inhibited AML cell proliferation, invasion, and migration while promoting apoptosis. It markedly downregulated FDX1, Lip-DLAT, Lip-DLST, and SDHB while upregulating HSP70 and intracellular Cu2⁺, inducing cuproptosis—an effect reversible by the cuproptosis inhibitor TTM. Res reduced glucose uptake, lactate production, ATP generation, and downregulated GLUT1, HK2, LDHA, and PKM2, thereby suppressing aerobic glycolysis-a process reversed by PFKFB3 overexpression. Furthermore, Res inhibited PI3K and AKT phosphorylation; the PI3K activator 740 Y-P counteracted Res-mediated effects while the PI3K inhibitor LY294002 enhanced them. In vivo experiments confirmed that Res treatment markedly diminished tumor size and mass, lowered Ki-67 proliferation marker, enhanced programmed cell death, suppressed PI3K/AKT signaling, decreased glycolytic enzyme levels, and elevated copper-dependent cell death mediators. Res exerts anti-AML effects by inhibiting the PI3K/AKT pathway while coordinately regulating aerobic glycolysis and cuproptosis in AML cells.

Graphical Abstract

Resveratrol effectively suppresses tumor progression by inhibiting the PI3K/AKT axis, downregulating aerobic glycolysis, and promoting cuproptosis.