Cellular retinol-binding protein-I inhibits PI3K/Akt signaling through a retinoic acid receptor-dependent mechanism that regulates p85-p110 heterodimerization.
Downregulation of the cellular retinol-binding protein-I (CRBP-I) occurs in breast and other human cancers, but its significance is not well understood. Recently, we showed that restoration of CRBP-I expression in transformed MTSV1-7 breast epithelial cells increased retinoic receptor activity, inhibited anoikis, promoted acinar differentiation and inhibited tumorigenicity, suggesting that CRBP-I suppresses tumor progression. However, the mechanism underlying these effects of CRBP-I was not elucidated. Here we demonstrate, using genetic and pharmacological approaches, that CRBP-I inhibits, in a retinoic acid receptor-dependent manner, the PI3K/Akt survival pathway. Inhibition of PI3K/Akt was necessary and sufficient to explain the antitumor effects of CRBP-I and was mediated by decreased p85 regulatory and p110 catalytic subunit heterodimerization. We present evidence consistent with the idea that this effect is due to CRBP-I inhibition of p85 phosphorylation at Y688. To our knowledge, this is the first demonstration of PI3K regulation at the level of p85-p110 heterodimerization. These findings lead us to hypothesize that CRBP-I downregulation in cancer promotes tumor progression through inhibition of retinoic acid receptor activity and derepression of PI3K/Akt signaling via a novel mechanism.
Farias
Eduardo F
EF
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. eduardo.farias@mssm.edu
Marzan
Chistine
C
Mira-y-Lopez
Rafael
R
D001940:Breast; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D002461:Cell Line, Transformed; D019281:Dimerization; D018450:Disease Progression; D005260:Female; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000502:physiology*; D054840:Retinol-Binding Proteins, Cellular; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; C518456:RBP1 protein, human; C494918:AKT1 protein, human