Reprogramming induced by isoliquiritigenin diminishes melanoma cachexia through mTORC2-AKT-GSK3β signaling
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Xiao-Yu Chen1, De-Fang Li2, Ji-Chun Han2, Bo Wang3, Zheng-Ping Dong2, Li-Na Yu2, Zhao-Hai Pan2, Chuan-Jun Qu2, Ying Chen2, Shi-Guo Sun1, Qiu-Sheng Zheng2
1College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, China
2Binzhou Medical University, Yantai, Shandong, 264003, China
3Key Laboratory of Xinjiang Endemic Phytomedicine Resources of Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, 832002, China
Qiu-Sheng Zheng, email: email@example.com
Shi-Guo Sun, email: firstname.lastname@example.org
Keywords: reprogramming, melanoma, cachexia, isoliquiritigenin, mTORC2-AKT-GSK3β signaling
Received: December 08, 2016 Accepted: March 15, 2017 Published: March 29, 2017
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.
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