Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 4A6.
Nat Commun. 2011;2:307. doi: 10.1038/ncomms1309.
PTEN dephosphorylates the 3-position phosphate of phosphatidylinositol 3,4,5 triphosphate (PIP(3)), thereby inhibiting AKT activation. Although attenuation of PTEN function has a major role in tumourigenesis, the underlying mechanisms remain unclear. Here we show that α-mannosidase 2C1 (MAN2C1) inhibits PTEN function in prostate cancer (PC) cells and is associated with a reduction in PTEN function in primary PC. MAN2C1 activates AKT and promotes the formation of PTEN-positive DU145 cell-derived xenograft tumours by imparing endogenous PTEN function. In 659 PC patients who were examined, ~60% of tumours were PTEN positive with elevated AKT activation. Of these, 80% display MAN2C1 overexpression that co-localizes with PTEN. Increases in MAN2C1 were detected only in PTEN-positive prostatic intraepithelial neoplasia and carcinomas, and showed a significant association with PC recurrence only in patients with PTEN-positive PCs. Mechanistically, MAN2C1 binds PTEN thereby inhibiting its PIP(3) phosphatase activity. These findings show that MAN2C1 function as a PTEN-negative regulator in PC cells.
PTEN 去磷酸化磷脂酰肌醇 3,4,5 三磷酸（PIP(3)）的 3 位磷酸基团，从而抑制 AKT 的激活。尽管 PTEN 功能的衰减在肿瘤发生中起着主要作用，但潜在的机制仍不清楚。在这里，我们表明 α-甘露糖苷酶 2C1（MAN2C1）在前列腺癌细胞中抑制 PTEN 功能，并与原发性 PC 中 PTEN 功能的降低有关。MAN2C1 通过损害内源性 PTEN 功能激活 AKT 并促进形成 PTEN 阳性的 DU145 细胞衍生的异种移植肿瘤。在检查的 659 名 PC 患者中，约 60%的肿瘤呈 PTEN 阳性，AKT 激活升高。在这些患者中，80%显示 MAN2C1 过表达，与 PTEN 共定位。仅在 PTEN 阳性前列腺上皮内瘤变和癌中检测到 MAN2C1 的增加，并且仅在 PTEN 阳性 PC 患者中与 PC 复发有显著相关性。从机制上讲，MAN2C1 与 PTEN 结合，从而抑制其 PIP(3)磷酸酶活性。这些发现表明 MAN2C1 在 PC 细胞中作为 PTEN 的负调节剂发挥作用。
