PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression

PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastatic development: Pten/RbPE:-/- mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:-/- mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node dissemination, correlating with upregulated phosphotyrosyl PI3K-p85α. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110β and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110α plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways. Four high-grade PIN lesions from Akap12/Rb-null mice (Pr_14273, Pr_14345, Pr_14354, Pr_14433). Two PC tumors from Pten/Rb-null mice (PT_T57, PT_173PT) are available in GSE90891 as samples GSM2417050 and GSM2417051, respectively.

PTEN缺失是前列腺癌（prostate cancer, PC）中最为频发的突变类型之一，被认为通过激活AKT（蛋白激酶B）通路推动疾病进展。然而，两款携带AKT激活联合Rb缺失的转基因PC模型却表现出迥异的转移表型：Pten/RbPE^(-/-) 小鼠可形成伴随高AKT2激活的系统性转移性腺癌；而缺失Src支架蛋白Akap12的RbPE^(-/-) 小鼠仅诱导高级别前列腺上皮内瘤变（high-grade prostatic intraepithelial neoplasia, PIN）与惰性淋巴结播散，该表型与磷酸化酪氨酸PI3K-p85α的上调存在相关性。本研究利用PTEN同源的PC细胞系证实，PTEN缺失与转移生长或运动能力相关的体外、体内实验参数均依赖p110β与AKT2，同时伴随已知PC转移抑制因子SMAD4的表达下调。与之相反，能够抑制上述致癌行为的PTEN表达，则与细胞更依赖p110α联合AKT1的表型相关。本研究数据表明，转移性前列腺癌的侵袭性由受不同Src激活或PTEN缺失通路调控的特定PI3K/AKT亚型组合所控制。本研究包含4个来自Akap12/Rb敲除小鼠的高级别PIN病变样本（Pr_14273、Pr_14345、Pr_14354、Pr_14433）；另有2株来自Pten/Rb敲除小鼠的PC肿瘤样本（PT_T57、PT_173PT），分别以GSM2417050与GSM2417051的样本编号收录于数据集GSE90891中。