Mst1, RanBP2 and eIF4G are new markers for in vivo PI3K activation in murine and human prostate.
Phosphatidylinositol 3-kinases (PI3Ks) constitute important regulators of signaling pathways. The PIK3CA gene encoding the p110-alpha catalytic subunit represents one of the highly mutated oncogenes identified in human cancer. Here, we report new markers for in vivo PI3K activation in prostate. To that end, we used a transgenic mouse line, which expresses a constitutively active p110-alpha subunit in the epithelial cells of the prostate. The activity of the PI3K pathway in the prostate was proven by assessing the phosphorylation of the PI3K direct target AKT1 and of the mTOR target eukaryotic translation initiation factor 4G (eIF4G). To establish also transcriptional ('late') targets of the PI3K pathway, we tested two genes, Mst1 and RanBP2, which we recently described as transcriptional targets of the growth factor platelet-derived growth factor-beta. We show that the levels of both proteins are elevated in transgenic animals. Additionally, we describe that the phosphorylation of AKT and eIF4G, as well as the elevation of the Mst1 and RanBP2 protein levels, can be inhibited in vivo in transgenic animals by the PI3K inhibitor LY294002. Finally, we performed human tissue microarray experiments with the four markers. Since they define overlapping but not identical subsets of the tested tissue panel, a combination of all four markers might lead to a more accurate diagnosis of the status of the PI3K-signaling cascade in cancer patients.
Renner
Oliver
O
Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), C/Melchor Fernandez Almagro3, Madrid, Spain.
Fominaya
Jesus
J
Alonso
Soledad
S
Blanco-Aparicio
Carmen
C
Leal
Juan F M
JF
Carnero
Amancio
A
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D000099317:Hippo Kinases
D014408:Biomarkers, Tumor; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D039603:Eukaryotic Initiation Factor-4G; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009025:Morpholines; D028861:Nuclear Pore Complex Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C094493:ran-binding protein 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C095566:STK4 protein, human; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse