title: Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress.
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.
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: De
authors.lastname: Huang
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Ronghui
authors.initials: R
authors.lastname: Yan
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.|Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, Hefei, Anhui 230001, China.
authors.forename: Songge
authors.initials: S
authors.lastname: Xing
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Gongwei
authors.initials: G
authors.lastname: Wu
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Hu
authors.affiliation: Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, Hefei, Anhui 230001, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.affiliation: State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015256:Coenzyme A-Transferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006885:Hydroxybutyrates / Q000032:analysis / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D001786:Blood Glucose; D016895:Culture Media, Serum-Free; D006885:Hydroxybutyrates; D007657:Ketone Bodies; D016329:Sp1 Transcription Factor; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase