Begley Lesa A, Kasina Sathish, Shah Rajal B, Macoska Jill A
Section of General Surgery, University of Michigan Ann Arbor, MI.
MMS Holdings, Inc. Canton, MI.
Am J Clin Exp Urol. 2015 Aug 8;3(2):91-9. eCollection 2015.
A key difference between normal and malignant prostate cells in vitro and in vivo is that both alleles of PTEN are largely intact in normal benign prostate glands and cultured epithelial cells, whereas one or both alleles of PTEN are mutant or deleted in the majority of prostate tumors and malignant prostate cancer cell lines. Intact PTEN suppresses phosphorylation of Akt downstream of PI3K activation in non-transformed cells whereas Akt phosphorylation is unimpeded in malignant cells that are often PTEN-deficient. We have previously shown that activation of the CXCL12/CXCR4 axis transactivates the EGFR to promote pro-proliferative signaling preferentially through the Raf/MEK/Erk pathway in benign prostate epithelial cells. These cells demonstrate little basal pAkt and these levels do not increase with CXCL12 stimulation because PTEN is intact and fully functional. Thus, inactivation of PTEN may be the critical factor that modulates downstream signaling and the specific CXCL12-stimulated proliferative responses of non-transformed and transformed prostate epithelial cells. Based on these data, we hypothesize that the CXCL12/CXCR4-mediated activation of downstream pro-proliferative signaling through the Raf/MEK/Erk or PI3K/Akt pathways is modulated by PTEN status.
体外和体内正常前列腺细胞与恶性前列腺细胞之间的一个关键差异在于,在正常良性前列腺腺体和培养的上皮细胞中,PTEN的两个等位基因基本完整,而在大多数前列腺肿瘤和恶性前列腺癌细胞系中,PTEN的一个或两个等位基因发生突变或缺失。完整的PTEN可抑制非转化细胞中PI3K激活下游的Akt磷酸化,而在通常缺乏PTEN的恶性细胞中,Akt磷酸化不受阻碍。我们之前已经表明,CXCL12/CXCR4轴的激活可反式激活EGFR,从而优先通过Raf/MEK/Erk途径促进良性前列腺上皮细胞中的促增殖信号传导。这些细胞几乎没有基础pAkt,并且由于PTEN完整且功能正常,这些水平不会随着CXCL12刺激而增加。因此,PTEN的失活可能是调节下游信号传导以及非转化和转化前列腺上皮细胞对CXCL12特异性刺激的增殖反应的关键因素。基于这些数据,我们假设CXCL12/CXCR4通过Raf/MEK/Erk或PI3K/Akt途径介导的下游促增殖信号传导的激活受PTEN状态的调节。