Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium
Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium
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DOI：
10.1073/pnas.0807691105
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发表时间：
2008-12-09
影响因子：
11.1
通讯作者：
Lee, Amy S.
中科院分区：
文献类型：
--
作者：
Fu, Yong;Wey, Shiuan;Lee, Amy S.
GRP 78/BiP最近成为侵袭性前列腺癌的新生物标志物。在这里，我们报告说，纯合子缺失Grp 78特异性在小鼠前列腺上皮细胞抑制前列腺肿瘤的发生，而不影响出生后前列腺的发育和生长。与Pten失活的小鼠前列腺中的浸润性腺癌相比，Grp 78和Pten双条件性敲除的小鼠前列腺表现出正常的组织学和细胞学。Pten缺失前列腺上皮中的AKT活化被Grp 78纯合缺失抑制，这与前列腺癌细胞系中GRP 78敲低抑制AKT磷酸化相对应。因此，GRP 78的失活可能代表了一种以前未描述的阻止前列腺癌和潜在的其他癌症的方法，这些癌症是由PTEN肿瘤抑制的丧失和/或致癌AKT的激活引起的。
GRP78/BiP has recently emerged as a novel biomarker for aggressive prostate cancer. Here, we report that homozygous deletion of Grp78 specifically in mouse prostate epithelium suppresses prostate tumorigenesis without affecting postnatal prostate development and growth. Mouse prostates with double conditional knockout of Grp78 and Pten exhibit normal histology and cytology, in contrast to the invasive adenocarcinoma in mouse prostates with Pten inactivation. AKT activation in Pten null prostate epithelium is inhibited by Grp78 homozygous deletion, corresponding with suppression of AKT phosphorylation by GRP78 knockdown in prostate cancer cell line. Thus, inactivation of GRP78 may represent a previously undescribed approach to stop prostate cancer and potentially other cancers resulting from the loss of PTEN tumor suppression and/or activation of the oncogenic AKT.