Convergence of three steroid receptor pathways in the mediation of nongenotoxic hepatocarcinogenesis.
The mechanisms by which peroxisome proliferators are able to regulate metabolic processes such as fat metabolism, while at the same time creating an environment for the development of hepatocellular carcinomas, is a central issue in the non-genotoxic carcinogenesis field. The convergence of two members of the steroid receptor family (peroxisome proliferator-activated receptor, PPAR; and retinoid X receptor, RXR) has provided strong support for an oxidative stress component in this carcinogenesis process, but has yet to define clearly a pathway for the classical tumor promotion events associated with peroxisome proliferation. The findings presented here integrate a third member of the steroid receptor family into this process and suggest a novel autocrine loop and mechanism for creating both oxidative stress and tumor promotion. A central regulatory component in this pathway is farnesol which has recently been shown to induce transcription mediated by the steroid receptor family member, farnesoid X receptor (FXR). In this report, it is clearly demonstrated that farnesol can also upregulate the transcriptional events of PPAR, but most likely through a different farnesoid metabolite, resulting in the regulation of an entirely different set of genetic components. Deregulation of the activities of these receptors offers a provocative mechanism for explaining the hepatocarcinogenic effects of peroxisome proliferators in chronically treated rodents.
O'Brien
M L
ML
Department of Biochemistry, University of Kentucky, Lexington, 40536, USA.
Rangwala
S M
SM
Henry
K W
KW
Weinberger
C
C
Crick
D C
DC
Waechter
C J
CJ
Feller
D R
DR
Noonan
D J
DJ
D042962:Acyl-CoA Oxidase; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis*; D005204:Farnesol / Q000378:metabolism / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D008113:Liver Neoplasms / Q000209:etiology*; D008148:Lovastatin / Q000494:pharmacology; D008830:Microbodies / Q000187:drug effects* / Q000502:physiology; D010088:Oxidoreductases / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology; D047488:Retinoid X Receptors; D012717:Sesquiterpenes; D014157:Transcription Factors / Q000187:drug effects* / Q000502:physiology
D000924:Anticholesteremic Agents; D005231:Fatty Acids, Unsaturated; D011106:Polyisoprenyl Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012717:Sesquiterpenes; D014157:Transcription Factors; D005204:Farnesol; C004808:farnesyl pyrophosphate; D002784:Cholesterol; C007702:farnesoic acid; D008148:Lovastatin; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase