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Concurrent induction of apoptosis and necroptosis in apigenin‑treated malignant mesothelioma cells: Reversal of Warburg effect through Akt inhibition and p53 upregulation

  • Authors:
    • Yoon-Jin Lee
    • Kwan-Sik Park
    • Su-Hak Heo
    • Moon-Kyun Cho
    • Sang-Han Lee
  • View Affiliations

  • Published online on: April 19, 2023     https://doi.org/10.3892/or.2023.8548
  • Article Number: 111
  • Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

A high dependence on aerobic glycolysis, known as the Warburg effect, is one of the metabolic features exhibited by tumor cells. Therefore, targeting glycolysis is becoming a very promising strategy for the development of anticancer drugs. In the present study, it was investigated whether pre‑adaptation of malignant mesothelioma (MM) cells to an acidic environment was associated with a metabolic shift to the Warburg phenotype in energy production, and whether apigenin targets acidosis‑driven metabolic reprogramming. Cell viability, glycolytic activity, Annexin V‑PE binding activity, reactive oxygen species (ROS) levels, mitochondrial membrane potential, ATP content, western blot analysis and spheroid viability were assessed in the present study. MM cells pre‑adapted to lactic acid were resistant to the anticancer drug gemcitabine, increased Akt activation, downregulated p53 expression, and upregulated rate‑limiting enzymes in glucose metabolism compared with their parental cells. Apigenin treatment increased cytotoxicity, Akt inactivation and p53 upregulation. Apigenin also reduced glucose uptake along with downregulation of key regulatory enzymes in glycolysis, increased ROS levels with loss of mitochondrial membrane potential, and downregulated the levels of complexes I, III and IV in the mitochondrial electron transport chain with intracellular ATP depletion, resulting in upregulation of molecules mediating apoptosis and necroptosis. Apigenin‑induced alterations of cellular responses were similar to those of Akt inactivation by Ly294002. Overall, the present results provide mechanistic evidence supporting the anti‑glycolytic and cytotoxic role of apigenin via inhibition of the PI3K/Akt signaling pathway and p53 upregulation.
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June-2023
Volume 49 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Lee Y, Park K, Heo S, Cho M and Lee S: Concurrent induction of apoptosis and necroptosis in apigenin‑treated malignant mesothelioma cells: Reversal of Warburg effect through Akt inhibition and p53 upregulation. Oncol Rep 49: 111, 2023.
APA
Lee, Y., Park, K., Heo, S., Cho, M., & Lee, S. (2023). Concurrent induction of apoptosis and necroptosis in apigenin‑treated malignant mesothelioma cells: Reversal of Warburg effect through Akt inhibition and p53 upregulation. Oncology Reports, 49, 111. https://doi.org/10.3892/or.2023.8548
MLA
Lee, Y., Park, K., Heo, S., Cho, M., Lee, S."Concurrent induction of apoptosis and necroptosis in apigenin‑treated malignant mesothelioma cells: Reversal of Warburg effect through Akt inhibition and p53 upregulation". Oncology Reports 49.6 (2023): 111.
Chicago
Lee, Y., Park, K., Heo, S., Cho, M., Lee, S."Concurrent induction of apoptosis and necroptosis in apigenin‑treated malignant mesothelioma cells: Reversal of Warburg effect through Akt inhibition and p53 upregulation". Oncology Reports 49, no. 6 (2023): 111. https://doi.org/10.3892/or.2023.8548