CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Alct/mTOR/SRESP1c and P38/PPARα pathways

Background & Aims: CD147 is a transmembrane glycoprotein which is highly expressed in various human cancers including hepatocellular carcinoma (HCC). A drug Licartin developed with (131)Iodine-labeled antibody against CD147 has been approved by the Chinese Food and Drug Administration (FDA) and enters into clinical use for HCC treatment. Increasing lines of evidence indicate that CD 147 is implicated in the metabolism of cancer cells, especially glycolysis. However, the molecular mechanism underlying the relationship between CD147 and aberrant tumor lipid metabolism remains elusive. Methods: We systematically investigated the role of CD147 in the regulation of lipid metabolism, including de novo lipogenesis and fatty acid beta-oxidation, in HCC cells and explored the underlying molecular mechanisms. Results: Bioinformatic analysis and experimental evidence demonstrated that CD147 significantly contributed to the reprogramming of fatty acid metabolism in HCC cells mainly through two mechanisms. On one hand, CD147 upregulated the expression of sterol regulatory element binding protein 1c (SREBP1c) by activating the Akt/mTOR signaling pathway, which in turn directly activated the transcription of major lipogenic genes FASN and ACC1 to promote de novo lipogenesis. On the other hand, CD147 downregulated peroxisome proliferator-activated receptor alpha (PPAR alpha) and its transcriptional target genes CPTIA and ACOX1 by activating the p38 MAPK signaling pathway to inhibit fatty acid beta-oxidation. Moreover, in vitro and in vivo assays indicated that the CD147-mediated reprogramming of fatty acid metabolism played a critical role in the proliferation and metastasis of HCC cells. Conclusion: Our findings demonstrate that CD147 is a critical regulator of fatty acid metabolism, which provides a strong line of evidence for this molecule to be used as a drug target in cancer treatment. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.