High-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB.
Many human epithelial cancers, particularly those with a poor prognosis, express high levels of fatty acid synthase (FAS), a key metabolic enzyme linked to the synthesis of membrane phospholipids in cancer cells. In view of the recent finding that in the human prostate cancer cell line LNCaP, overexpression of FAS can be largely attributed to constitutive activation of the phosphatidylinositol-3 (PI3) kinase/Akt kinase pathway, the activation status of the Akt pathway, and whether this activation coincides with increased FAS expression, was examined in clinical prostate cancer tissues. Using well-preserved frozen prostatic needle biopsies and a sensitive Envision detection technique, S473-phosphorylated Akt (pAkt) was found in 11/23 low-grade prostatic intraepithelial neoplasia (PIN) lesions, in all (36/36) high-grade PINs, and in all (86/86) invasive carcinomas. Non-neoplastic tissues were negative. Interestingly, in low-grade PINs and low-grade carcinomas, pAkt was mainly cytoplasmic or membrane-bound and was associated with moderate elevation of FAS expression. In 24/36 high-grade PINs and 82/88 invasive carcinomas, pAkt was found at least partly in the nucleus. Greater nuclear pAkt staining, and higher FAS expression, correlated with a higher Gleason score. In the light of previous findings that pAkt plays a causative role in the overexpression of FAS in cancer cells in culture, these data strongly suggest that high-level expression of FAS in prostate cancer tissues is linked to phosphorylation and nuclear accumulation of Akt.
Van de Sande
Tine
T
Laboratory for Experimental Medicine and Endocrinology, University of Leuven, B-3000 Leuven, Belgium.
Roskams
Tania
T
Lerut
Evelyne
E
Joniau
Steven
S
Van Poppel
Hein
H
Verhoeven
Guido
G
Swinnen
Johannes V
JV
D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D064429:Fatty Acid Synthases / Q000378:metabolism*; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007124:Immunoenzyme Techniques; D008297:Male; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt
D007106:Immune Sera; D011518:Proto-Oncogene Proteins; D064429:Fatty Acid Synthases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt