Reprogramming induced by isoliquiritigenin diminishes melanoma cachexia through mTORC2-AKT-GSK3β signaling.

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.

• Authors: Xiao-Yu Chen, De-Fang Li, Ji-Chun Han, Bo Wang, Zheng-Ping Dong, Li-Na Yu, Zhao-Hai Pan, Chuan-Jun Qu, Ying Chen, Shi-Guo Sun, Qiu-Sheng Zheng
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 21 Pg. 34565-34575 (May 23 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28410220 (Publication Type: Journal Article)

Chemical References

• Chalcones
• Enzyme Inhibitors
• Morpholines
• Pyrimidines
• Lactic Acid
• Ku 0063794
• isoliquiritigenin
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• Glucose
• Oxygen

Topics

• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chalcones (pharmacology)
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glucose (metabolism)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Lactic Acid (metabolism)
• Mechanistic Target of Rapamycin Complex 2 (metabolism)
• Melanoma (drug therapy, metabolism)
• Morpholines (pharmacology)
• Oxygen (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)