Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Parkville, VIC 3010, Australia.
Mol Cell. 2020 Oct 15;80(2):279-295.e8. doi: 10.1016/j.molcel.2020.09.027.
The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. While the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Here, using knockin (KI) mice harboring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. Thus, we find that the dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN loss-driven cancers.
PTEN 肿瘤抑制因子通过调节各种分子靶标的功能来控制细胞死亡和存活。虽然 PTEN 脂质磷酸酶活性对 PtdIns(3,4,5)P3 的作用和 PI3K 途径的抑制作用已得到很好的描述，但 PTEN 蛋白磷酸酶活性的生物学相关性仍未确定。在这里，我们使用携带与癌症相关且具有功能相关性的错义突变的基因敲入 (KI) 小鼠表明，尽管 PTEN 脂质磷酸酶功能的丧失与致癌性 PI3K 合作促进了快速的乳腺肿瘤发生，但 PTEN 蛋白磷酸酶活性的额外丧失引发了广泛的细胞死亡反应，在早期和晚期乳腺肿瘤中都很明显。组学和药物靶向研究表明，PI3Ks 作用于降低糖皮质激素受体 (GR) 的水平，而 PTEN 蛋白磷酸酶活性的丧失可以挽救 GR 水平，从而抑制细胞存活。因此，我们发现 PI3K 和 PTEN 对 GR 的双重调节作用可以作为变阻器加以利用，用于治疗由 PTEN 缺失驱动的癌症。
