Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression
Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression
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DOI：
10.1074/jbc.m003145200
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发表时间：
2000-08-11
影响因子：
4.8
通讯作者：
Neubauer, BL
中科院分区：
文献类型：
--
作者：
Graff, JR;Konicek, BW;Neubauer, BL
PTEN 肿瘤抑制基因在人类前列腺癌中经常失活，特别是在更晚期的癌症中，这表明受 PTEN 负调控的 AKT/蛋白激酶 B (PKB) 激酶可能参与人类前列腺癌的进展。我现在表明，在由雄激素依赖性 LNCaP 细胞系的异种移植肿瘤建立的不依赖雄激素的前列腺特异性抗原阳性前列腺癌细胞 (LNAI 细胞) 中，ART 激活和活性显着增加。这些 LNAI 细胞表现出整合素连接激酶表达增加，推测该激酶与 AKT 激活/Ser-473 磷酸化以及 AKT 靶蛋白 BAD 磷酸化增加有关。此外，LNAI 细胞中 p27(Kip1) 细胞周期调节因子的表达减少，这与 AKT 直接抑制 AFX/Forkhead 介导的 p27(Kip1) 转录的观点一致。为了直接评估 AKT 活性增加对前列腺癌进展的影响，在 LNCaP 细胞中过表达激活的 hAKT1 突变体，导致异种移植肿瘤生长增加 B 倍。与 LNAI 细胞一样，这些转染子的 p271(Kip1) 表达显着降低。总之，这些数据表明前列腺肿瘤进展和雄激素独立性中 AKT 活性增加，并表明与前列腺癌进展反复相关的 p27 (Kip1) 表达减少可能是 AKT 活性增加的结果。
The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. me now show that ART activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a B-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p271(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.