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Extracellular Citrate Treatment Induces HIF1α Degradation and Inhibits the Growth of Low-Glycolytic Hepatocellular Carcinoma under Hypoxia

 Seon Yoo Kim  ;  Dongwoo Kim  ;  Jisu Kim  ;  Hae Young Ko  ;  Won Jin Kim  ;  Youngjoo Park  ;  Hye Won Lee  ;  Dai Hoon Han  ;  Kyung Sik Kim  ;  Sunghyouk Park  ;  Misu Lee  ;  Mijin Yun 
 CANCERS, Vol.14(14) : 3355, 2022-07 
Journal Title
Issue Date
SLC13A5/NaCT ; cancer metabolism ; citrate ; hepatocellular carcinoma ; hypoxia
HCC is well known for low glycolysis in the tumors, whereas hypoxia induces glycolytic phenotype and tumor progression. This study was conducted to evaluate the expression of SLCs in human HCCs and investigated whether extracellular nutrient administration related to SLCs in low-glycolytic HCC can prevent hypoxic tumor progression. SLCs expression was screened according to the level of glycolysis in HCCs. Then, whether extracellular nutrient treatment can affect hypoxic tumor progression, as well as the mechanisms, were evaluated in an in vitro cell line and an in vivo animal model. Low-glycolytic HCCs showed high SLC13A5/NaCT and SLC16A1/MCT1 but low SLC2A1/GLUT1 and HIF1α/HIF1α expression. Especially, high SLC13A5 expression was significantly associated with good overall survival in the Cancer Genome Atlas (TCGA) database. In HepG2 cells with the highest NaCT expression, extracellular citrate treatment upon hypoxia induced HIF1α degradation, which led to reduced glycolysis and cellular proliferation. Finally, in HepG2-animal models, the citrate-treated group showed smaller tumor with less hypoxic areas than the vehicle-treated group. In patients with HCC, SLC13A5/NaCT is an important SLC, which is associated with low glycolysis and good prognosis. Extracellular citrate treatment induced the failure of metabolic adaptation to hypoxia and tumor growth inhibition, which can be a potential therapeutic strategy in HCCs.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sik(김경식) ORCID logo https://orcid.org/0000-0001-9498-284X
Kim, Dongwoo(김동우) ORCID logo https://orcid.org/0000-0002-1723-604X
Yun, Mijin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Hye Won(이혜원) ORCID logo https://orcid.org/0000-0002-3552-3560
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
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