Inhibition of fatty acid synthase by luteolin post-transcriptionally down-regulates c-Met expression independent of proteosomal/lysosomal degradation.
The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in the progression of several cancers and associated with increased tumor invasion and metastatic potential. We determined previously that the polyphenol epigallocatechin-3-gallate inhibited HGF-induced c-Met phosphorylation in a variety of tumor cell lines in part by disrupting lipid rafts. Fatty acid synthase (FASN) is implicated in cancer progression and may regulate lipid raft function. We therefore examined the effects of luteolin, a potent FASN inhibitor, on c-Met signaling. Luteolin blocked HGF-induced c-Met phosphorylation and scattering of DU145 prostate cancer cells, but inhibition required at least a 4 h preincubation time. Western blot analysis indicated that inhibition of HGF-induced scattering by luteolin occurred coincident with reduction of total c-Met protein in DU145 cells. In addition, luteolin-induced c-Met down-regulation was mimicked by a pharmacologic inhibitor of FASN, C75, or short hairpin RNA knockdown of FASN. Consistent with a role for FASN, loss of c-Met in cells treated with C75 or luteolin was prevented by exogenous addition of palmitate. Luteolin-induced loss of c-Met primarily occurred at a post-transcriptional level and involved cell surface internalization but did not involve translation inhibition, nor was it dependent on the activity of the 26S proteosome or acidic lysosomes. Taken together, our study shows a novel connection between FASN activity and c-Met protein expression and suggests that luteolin could act as a novel HGF/c-Met inhibitor by reducing expression of this receptor.
Coleman
David T
DT
Department of Microbiology and Immunology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Bigelow
Rebecca
R
Cardelli
James A
JA
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D017228:Hepatocyte Growth Factor; D064429:Fatty Acid Synthases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D047311:Luteolin