Inhibition of mTORC1 signaling sensitizes hepatocellular carcinoma cells to glycolytic stress.
Reprogrammed glucose metabolism, especially glycolysis, is profoundly implicated in tumor development or metastasis. As the interconnectedness and flexibility of metabolic signaling, targeting a metabolic signaling molecule may have limited anti-tumor effects. Here, Gene set enrichment analysis (GSEA) was used to explore the accompanied effectors of glycolysis in hepatocellular carcinoma (HCC). Based on the expression of lactate dehydrogenase A (LDHA), a key enzyme in catalyzing pyruvate into lactate, the glycolytic ability of HCC was defined as low group and high group. GSEA of two independent GEO datasets showed that mTORC1 signaling was the most striking metabolic alternations in high group. Pharmacological inhibition of mTORC1 signaling with rapamycin decreased LDHA level and glycolytic capacity of six HCC cell lines. Furthermore, c-Myc was identified as a downstream target of mTORC1 signaling and mediated mTORC1-induced LDHA expression. Importantly, rapamycin sensitized HCC cells to the glycolysis inhibitor 2-deoxyglucose (2-DG) invitroandin vivo. Meanwhile, genetic silencing several other downstream targets of mTORC1 signaling (TFEB, SREBP-1 and SKAR) failed to enhance or faintly influenced the cytotoxic effects of 2-DG. These results demonstrate that combining rapamycin with 2-DG holds significant promise as prospective clinical treatment in HCC.
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Xin
X
Zhao
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Peng
P
Jiang
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Xiang
X
Deng
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Zhonghu
Z
Li
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Feng
F
Tian
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Fei
F
Guo
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Xiaowu
X
Li
Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University Chongqing 400038, PR China.
Shuguang
S
Wang
glycolysis; hepatocellular carcinoma; lactate dehydrogenase a; mTOR signaling