Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

De Huang, Tingting Li, Lin Wang, Long Zhang, Ronghui Yan, Kui Li, Songge Xing, Gongwei Wu, Lan Hu, Weidong Jia, Sheng Cai Lin, Chi V. Dang, Libing Song, Ping Gao, Huafeng Zhang

Research output: Contribution to journalArticle

Abstract

Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.

Original languageEnglish (US)
Pages (from-to)1112-1130
Number of pages19
JournalCell Research
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2016

Keywords

  • AKT
  • AMPK
  • HCC
  • OXCT1
  • autophagy
  • ketone bodies

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Huang, D., Li, T., Wang, L., Zhang, L., Yan, R., Li, K., Xing, S., Wu, G., Hu, L., Jia, W., Lin, S. C., Dang, C. V., Song, L., Gao, P., & Zhang, H. (2016). Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress. Cell Research, 26(10), 1112-1130. https://doi.org/10.1038/cr.2016.109