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Reprogramming induced by isoliquiritigenin diminishes melanoma cachexia through mTORC2-AKT-GSK3β signaling
Xiao-Yu Chen1, De-Fang Li2, Ji-Chun Han2
1College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Abstract:
Isoliquiritigenin (ISL), a member of the flavonoids, is known to have anti-tumor activity in vitro and in vivo. The effect of ISL on reprogramming in cancer cells, however, remains elusive. In this study, we investigated the effect of ISL on reprogramming in human melanoma A375 cells. ISL (15 μg/ml) significantly inhibited A375 cell proliferation, anchorage independent cell proliferation and G2/M cell cycle arrest after ISL exposure for 24 h. However, there were no significant changes in apoptosis rate. Terminal differentiation indicators (melanin content, melanogenesis mRNA expression, tyrosinase (TYR) activity) were all up-regulated by ISL treatment. In ISL-treated cells, glucose uptake, lactate levels and mRNA expression levels of GLUT1 and HK2 were significantly decreased, and accompanied by an increase in O2 consumption rate (OCR) and adenosine triphosphate (ATP) deficiency. Protein expression levels of mTORC2-AKT-GSK3β signaling pathway components (mTOR, p-mTOR, RICTOR, p-AKT, p-GSK3β) decreased significantly after ISL treatment. Co-treatment of ISL and the mTOR-specific inhibitor Ku-0063794 had a synergistic effect on the inhibition of proliferation, and increased melanin content and TYR activity. Glucose uptake and lactate levels decreased more significantly than treatment with ISL alone. These findings indicate that ISL induced reprogramming in A375 melanoma cells by activating mTORC2-AKT-GSK3β signaling.
Insights
Isoliquiritigenin (ISL) reprograms human melanoma cells, inhibiting proliferation and promoting differentiation by affecting glucose metabolism and activating the mTORC2-AKT-GSK3β pathway. This suggests ISL
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Flavonoids, including Isoliquiritigenin (ISL), exhibit known anti-tumor properties.
- The impact of ISL on cancer cell reprogramming remains largely unexplored.
- Melanoma is a significant form of skin cancer with diverse cellular behaviors.
Purpose of the Study:
- To investigate the effect of Isoliquiritigenin (ISL) on the reprogramming of human melanoma A375 cells.
- To elucidate the molecular mechanisms underlying ISL-induced cellular changes in melanoma.
- To assess the potential of ISL as a therapeutic agent for melanoma.
Main Methods:
- Treatment of human melanoma A375 cells with ISL (15 μg/ml) for 24 hours.
- Analysis of cell proliferation, cell cycle, apoptosis, and terminal differentiation markers.
- Measurement of glucose uptake, lactate production, oxygen consumption rate (OCR), and ATP levels.
- Western blot analysis to assess the mTORC2-AKT-GSK3β signaling pathway.
- Co-treatment experiments with ISL and an mTOR inhibitor (Ku-0063794).
Main Results:
- ISL significantly inhibited A375 cell proliferation and induced G2/M cell cycle arrest without affecting apoptosis.
- ISL upregulated terminal differentiation indicators, including melanin content and tyrosinase activity.
- ISL decreased glucose uptake and lactate production, increasing oxygen consumption and causing ATP deficiency.
- ISL treatment led to decreased protein expression of mTORC2-AKT-GSK3β pathway components.
- Combined ISL and mTOR inhibitor treatment showed synergistic effects on proliferation inhibition and differentiation induction.
Conclusions:
- Isoliquiritigenin (ISL) induces reprogramming in human melanoma A375 cells.
- ISL promotes differentiation and inhibits proliferation, potentially by modulating cellular metabolism and the mTORC2-AKT-GSK3β pathway.
- ISL demonstrates potential as a therapeutic agent for melanoma, warranting further investigation.