ABSTRACT
Lipid accumulation exacerbates tumor development, as it fuels the proliferative growth of cancer cells. The role of medium-chain acyl-CoA dehydrogenase (ACADM), an enzyme that catalyzes the first step of mitochondrial fatty acid oxidation, in tumor biology remains elusive. Therefore, investigating its mode of dysregulation can shed light on metabolic dependencies in cancer development. In hepatocellular carcinoma (HCC), ACADM was significantly underexpressed, correlating with several aggressive clinicopathologic features observed in patients. Functionally, suppression of ACADM promoted HCC cell motility with elevated triglyceride, phospholipid, and cellular lipid droplet levels, indicating the tumor suppressive ability of ACADM in HCC. Sterol regulatory element-binding protein-1 (SREBP1) was identified as a negative transcriptional regulator of ACADM. Subsequently, high levels of caveolin-1 (CAV1) were observed to inhibit fatty acid oxidation, which revealed its role in regulating lipid metabolism. CAV1 expression negatively correlated with ACADM and its upregulation enhanced nuclear accumulation of SREBP1, resulting in suppressed ACADM activity and contributing to increased HCC cell aggressiveness. Administration of an SREBP1 inhibitor in combination with sorafenib elicited a synergistic antitumor effect and significantly reduced HCC tumor growth in vivo. These findings indicate that deregulation of fatty acid oxidation mediated by the CAV1/SREBP1/ACADM axis results in HCC progression, which implicates targeting fatty acid metabolism to improve HCC treatment. SIGNIFICANCE: This study identifies tumor suppressive effects of ACADM in hepatocellular carcinoma and suggests promotion of ß-oxidation to diminish fatty acid availability to cancer cells could be used as a therapeutic strategy.
Subject(s)
Acyl-CoA Dehydrogenase/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/pathology , Caveolin 1/metabolism , Fatty Acids/chemistry , Gene Expression Regulation, Neoplastic , Sterol Regulatory Element Binding Protein 1/metabolism , Acyl-CoA Dehydrogenase/genetics , Acyl-CoA Dehydrogenase/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Caveolin 1/genetics , Cell Proliferation , Humans , Lipid Metabolism , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Oxidation-Reduction , Prognosis , Sterol Regulatory Element Binding Protein 1/genetics , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
dpy-11 encodes a thioredoxin-like molecule that is important for both body and male sensory ray morphogenesis in Caenorhabditis elegans. A mutant allele, s287, has a point mutation with its start codon, AUG, converted into AUA, presumably leading to null function. Since only a weak loss-of-function phenotype was observed, we tested whether an alternative start codon or the converted AUA could be used for translation initiation with reduced efficiency. Based on a functional assay of mutant phenotype complementation and biochemical analysis examining the in vivo synthesis of wild-type and mutant proteins, we conclude that AUA can be used as a less-efficient start codon for initiating translation of DPY-11. Our results also provide direct evidence that the body hypodermis and male tail of C. elegans have differential requirements of dpy-11 activity for their respective normal morphogenesis.
Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/metabolism , Dermis/metabolism , Membrane Proteins/genetics , Membrane Proteins/physiology , Mutation , Alleles , Amino Acid Sequence , Animals , Animals, Genetically Modified , Base Sequence , Blotting, Western , Codon, Initiator , DNA, Complementary/metabolism , Genetic Complementation Test , Male , Molecular Sequence Data , Peptides/chemistry , Phenotype , Point Mutation , Protein Biosynthesis , Protein Sorting Signals , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Sensory ray morphogenesis in C. elegans requires active cellular interaction regulated by multiple genetic activities. We report here the cloning of one of these genes, dpy-11, which encodes a membrane-associated thioredoxin-like protein. The DPY-11 protein is made exclusively in the hypodermis and resides in the cytoplasmic compartment. Whereas the TRX domain of DPY-11 displays a catalytic activity in vitro, mapping of lesions in different mutant alleles and functional analysis of deletion transgenes reveal that both this enzymatic activity and transmembrane topology are essential for determining body shape and ray morphology. Based on the abnormal features in both the expressing and non-expressing ray cells, we propose that the DPY-11 is required in the hypodermis for modification of its substrates. In turn, ray cell interaction and the whole morphogenetic process can be modulated by these substrate molecules.
