Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14209, USA.
American Society of Human Genetics, Rockville, MD, 20852, USA.
Oncogene. 2024 Jan;43(1):22-34. doi: 10.1038/s41388-023-02875-4. Epub 2023 Oct 24.
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/Rb mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas Rb 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.
PTEN 缺失是前列腺癌（PC）最常见的突变之一，据推测它通过 AKT 激活驱动疾病进展。然而，两种 Akt 激活加 Rb 缺失的转基因 PC 模型表现出不同的转移发展：Pten/Rb 小鼠产生全身性转移性腺癌，AKT2 激活水平高，而 Rb 小鼠中Src 支架蛋白 Akap12 缺失，诱导高级别前列腺上皮内瘤变和惰性淋巴结播散，与磷酸化酪氨酸 PI3K-p85α 的上调相关。使用前列腺癌细胞同基因的 PTEN，我们表明 PTEN 缺失与体外和体内转移生长或运动的参数对 p110β 和 AKT2 的依赖性相关，并且与已知的前列腺癌转移抑制因子 SMAD4 的下调相关。相比之下，PTEN 的表达抑制了这些致癌行为，与对 p110α 加 AKT1 的更大依赖性相关。我们的数据表明，转移性 PC 的侵袭性受特定的 PI3K/AKT 同工型组合控制，这些组合受不同的Src 激活或 PTEN 缺失途径影响。
