Chenran Wang1, Michael A Haas2, Syn Kok Yeo2, Ritama Paul2, Fuchun Yang2, Subrahmanya Vallabhapurapu3, Xiaoyang Qi3, David R Plas2, Jun-Lin Guan2. 1. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. wang2cr@ucmail.uc.edu. 2. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 3. Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Abstract
BACKGROUND: Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied. METHODS: Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma. RESULTS: We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1. CONCLUSIONS: This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.
BACKGROUND: Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied. METHODS: Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma. RESULTS: We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1. CONCLUSIONS: This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.
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