Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2.
Insulin-like growth factor 2 (IGF2) is a potent mitogen whose deregulation plays a role in developing liver, breast, and prostate cancers. Here, we take a small-molecule approach to investigate molecular pathways that modulate IGF2 signaling, by using chromeceptin, a synthetic molecule that selectively impairs the viability and growth of IGF2-overexpressing hepatocellular carcinoma cells. Affinity purification revealed that chromeceptin binds to multifunctional protein 2 (MFP-2), a seemingly multifunctional enzyme implicated in peroxisomal beta-oxidation. The small molecule-protein interaction stimulates the expression of IGF binding protein 1 (IGFBP-1) and suppressor of cytokine signaling-3 (SOCS-3), two cellular attenuators of the IGF signals, through activation of signal transducers and activators of transcription 6 (STAT6). The results underline the importance of STATs in IGF/insulin regulation, and they implicate a new pathway for STAT6 activation that is amenable to small-molecule intervention.
Choi
Yongmun
Y
TheVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Shimogawa
Hiroki
H
Murakami
Koji
K
Ramdas
Latha
L
Zhang
Wei
W
Qin
Jun
J
Uesugi
Motonari
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000494:pharmacology*; D000818:Animals; D004746:Enoyl-CoA Hydratase / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000494:pharmacology*; D010084:Oxidation-Reduction; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D018970:Insulin-Like Growth Factor Binding Protein 1; D009097:Multienzyme Complexes; D050800:STAT6 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D007335:Insulin-Like Growth Factor II; D015067:17-Hydroxysteroid Dehydrogenases; C491288:Hsd17b4 protein, mouse; D064029:Peroxisomal Multifunctional Protein-2; D004746:Enoyl-CoA Hydratase