Hexokinase II as a Potential Target of Apigenin Through the Induction of Apoptosis and Necroptosis in Malignant Mesothelioma

Our plain-English summary of Hexokinase II as a Potential Target of Apigenin Through the Induction of Apoptosis and Necroptosis in Malignant Mesothelioma, by M.K. Cho, S.H. Lee, H.S. Nam, et al (Nutrients, 2026).

The study

• Authors: M.K. Cho, S.H. Lee, H.S. Nam, Y.J. Lee
• Journal: Nutrients
• Published: 2026;18(19)
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Lactate-acclimated MSTO-211HAcT and H2452AcT malignant mesothelioma (MM) cells were previously found to tolerate gemcitabine more readily than their parental cells while remaining sensitive to apigenin. We examined whether changes in glucose metabolism and HKII contribute to the apigenin response. Methods: Apigenin was evaluated in monolayer and spheroid cultures and in a xenograft model; HKII was also silenced in the acclimated cells. Results: Apigenin reduced cell viability, p-AKT (Ser473), glycolysis-associated proteins including HKII, and mitochondrial electron transport chain proteins, while increasing p53 and markers of cell death. Tumor growth and selected metabolic proteins were reduced in the xenograft model. HKII silencing reduced cell viability and glucose utilization, lowered cellular ATP, altered mitochondrial membrane potential, and increased markers of apoptosis and necroptosis. Conclusions: HKII-associated metabolism contributes to survival of lactate-acclimated MM cells, and apigenin affects this metabolic phenotype. Direct targeting of HKII by apigenin and the complete mitochondrial apoptotic pathway require further study.

In plain English

This was a laboratory study of cells and mice. It did not study people or asbestos exposure. The authors tested apigenin, a plant flavonoid, on two human malignant mesothelioma cell lines (MSTO-211H and H2452) that had been adapted to lactic acid. They used flat cell cultures, three-dimensional cell clusters (spheroids), and tumors grown in 12 nude mice. After 48 hours, apigenin reduced cell viability. The estimated concentrations that halved viability were 47.2 and 56.3 µM in the two lines. At 30 µM, spheroid viability was 58.2% and 69.6% of control. In mice, apigenin, cisplatin, or both, injected into the tumors, reduced tumor volume compared with vehicle. When the authors silenced the enzyme hexokinase II, cell growth fell by about 23.6% and 16.6%, and by about 52.3% and 46.8% when apigenin was added. Cellular energy (ATP) was also lower. The authors concluded that hexokinase II-linked metabolism is associated with these cells' survival. They said apigenin's direct target remains unresolved and that mouse tumors differ from human tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell culture experiments (monolayer and spheroid cultures, gene silencing with siRNA) and an animal experiment (mouse xenograft model)
• Who was studied: Two human malignant mesothelioma cell lines, MSTO-211H and H2452, obtained from ATCC and adapted to lactic acid (called MSTO-211HAcT and H2452AcT). Also 12 male BALB/c nude mice carrying MSTO-211HAcT tumors under the skin, randomized into vehicle, apigenin, cisplatin, and apigenin-plus-cisplatin groups.
• Exposure: Apigenin (a plant flavonoid), given to cells at 0 to 60 µM for 48 h. In mice, apigenin 20 mg/kg and/or cisplatin 5 mg/kg were injected into the tumors three times weekly for 24 days. Hexokinase II was also silenced with siRNA. Asbestos exposure was not studied.
• Main results:
  • In monolayer cultures, apigenin reduced viability after 48 h. Estimated IC50 values were 47.2 µM for MSTO-211HAcT and 56.3 µM for H2452AcT.
  • After 30 µM apigenin for 48 h, spheroid viability was 58.2% of control for MSTO-211HAcT and 69.6% for H2452AcT.
  • Apigenin was associated with lower p-AKT (Ser473) and higher p53 in both cell lines, in both culture types. HKII, PFKP, PDH and several OXPHOS proteins also decreased.
  • In mouse xenografts, intratumoral apigenin and cisplatin, given alone or together, reduced tumor volume relative to vehicle. All mice survived.
  • Tumors in the apigenin-containing groups showed increases in the Bax/Bcl-2 ratio, cleaved caspase-3, p-MLKL (Ser358) and p-RIP3 (Ser227), which the authors treat as markers of apoptosis and necroptosis. The changes with cisplatin alone were smaller.
  • Compared with control siRNA, HKII silencing reduced growth by about 23.6% in MSTO-211HAcT and 16.6% in H2452AcT cells. With apigenin added, the reductions were about 52.3% and 46.8% (p less than 0.05).
  • After HKII silencing, glucose remaining in the culture medium was approximately 12.0% (MSTO-211HAcT) and 13.3% (H2452AcT) higher than in controls. With apigenin added, it was approximately 64.6% and 49.6% higher.
  • After HKII silencing, the fraction of cells with depolarized mitochondria rose from 1.44% to 28.77% in MSTO-211HAcT and from 2.13% to 26.89% in H2452AcT. Adding apigenin increased this further.
  • Cellular ATP was highest in controls. It was lower after HKII knockdown, lower again with apigenin, and lowest with their combination.
• The authors' conclusion: The authors concluded that, in lactate-acclimated mesothelioma models, apigenin reduced glycolysis-associated proteins and cellular energy measures and increased markers of apoptosis and necroptosis. They found that HKII silencing produced partly overlapping effects, supporting an association between HKII-dependent metabolism and cell survival. They stated that apigenin's direct target and the precise mitochondrial apoptotic sequence remain unresolved and warrant further study.
• Limitations the authors state:
  • The findings do not establish HKII as a direct molecular binding target of apigenin.
  • Body weight and general appearance of the mice cannot by themselves establish systemic safety.
  • Mouse xenografts differ from human primary tumors in immune function, stromal composition, implantation site and growth kinetics.
  • Caspase-9 activation, cytochrome c release and the effect of inhibiting this pathway were not measured, so the full intrinsic apoptotic cascade is not established.
  • The causal role of p-AKT (Ser473) and p53 relative to HKII was not tested.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma, Gemcitabine.

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• Pifithrin-μ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial-mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis — Y.J. Lee, K.S. Park, et al. (2019)
• Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells — Y.J. Lee, K.S. Park, et al. (2020)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)
• Cariporide Enhances the DNA Damage and Apoptosis in Acid-tolerable Malignant Mesothelioma H-2452 Cells — Y.J. Lee, J.H. Bae, et al. (2017)
• Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction — K.E. Hwang, Y.S. Kim, et al. (2014)

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