Nakatani K, Thompson D A, Barthel A, Sakaue H, Liu W, Weigel R J, Roth R A
Departments of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.
J Biol Chem. 1999 Jul 30;274(31):21528-32. doi: 10.1074/jbc.274.31.21528.
We measured the insulin-stimulated amount of Akt1, Akt2, and Akt3 enzymatic activities in four breast cancer cell lines and three prostate cancer cell lines. In the estrogen receptor-deficient breast cancer cells and the androgen-insensitive prostate cells, the amount of Akt3 enzymatic activity was approximately 20-60-fold higher than in the cells that were estrogen- or androgen-responsive. In contrast, the levels of Akt1 and -2 were not increased in these cells. The increase in Akt3 enzyme activity correlated with an increase in both Akt3 mRNA and protein. In a prostate cancer cell line lacking the tumor suppressor PTEN (a lipid and protein phosphatase), the basal enzymatic activity of Akt3 was constitutively elevated and represented the major active Akt in these cells. Finally, reverse transcription-PCR was used to examine the Akt3 expression in 27 primary breast carcinomas. The expression levels of Akt3 were significantly higher in the estrogen receptor-negative tumors in comparison to the estrogen receptor-positive tumors. To see if the increase in Akt3 could be due to chromosomal abnormalities, the Akt3 gene was assigned to human chromosome 1q44 by fluorescence in situ hybridization and radiation hybrid cell panel analyses. These results indicate that Akt3 may contribute to the more aggressive clinical phenotype of the estrogen receptor-negative breast cancers and androgen-insensitive prostate carcinomas.
我们测定了四种乳腺癌细胞系和三种前列腺癌细胞系中胰岛素刺激的Akt1、Akt2和Akt3酶活性水平。在雌激素受体缺陷型乳腺癌细胞和雄激素不敏感型前列腺癌细胞中，Akt3酶活性水平比雌激素或雄激素反应型细胞高约20 - 60倍。相比之下，这些细胞中Akt1和Akt2的水平并未升高。Akt3酶活性的增加与Akt3 mRNA和蛋白的增加相关。在一个缺乏肿瘤抑制因子PTEN（一种脂质和蛋白磷酸酶）的前列腺癌细胞系中，Akt3的基础酶活性持续升高，且是这些细胞中主要的活性Akt。最后，采用逆转录-聚合酶链反应检测了27例原发性乳腺癌中Akt3的表达。与雌激素受体阳性肿瘤相比，雌激素受体阴性肿瘤中Akt3的表达水平显著更高。为了探究Akt3的增加是否可能归因于染色体异常，通过荧光原位杂交和辐射杂交细胞板分析将Akt3基因定位于人类染色体1q44。这些结果表明，Akt3可能促成了雌激素受体阴性乳腺癌和雄激素不敏感型前列腺癌更具侵袭性的临床表型。
