Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden; Department of Pharmacology, Medical University of South Carolina, United States.
Biomed Pharmacother. 2020 Jul;127:110112. doi: 10.1016/j.biopha.2020.110112. Epub 2020 Apr 12.
Akt kinase regulates several cellular processes, among them growth, proliferation and survival, and has been correlated to neoplastic disease. We report here crosstalk between several Akt regulatory phosphatases that controls the level of the activated form (phosphorylated) of Akt and affects tumor cell aggressiveness. In prostate cancer cell lines, we observed that transient transfection of PTEN decreased the endogenous level of PHLPPs and in contrast, the transient transfection of PHLPPs decreased the endogenous level of PTEN. Furthermore, silencing of PTEN by siRNA resulted in increased PHLPP levels. This phenomenon was not seen in non-transformed cells or in prostate stem cells. This crosstalk promoted cancer cell invasion and was controlled by epigenetically regulated processes where activation of miRs (miR-190 and miR214), the polycomb group of proteins and DNA methylation were involved. The purinergic P2X4 receptor, which has been shown to have a role in wound healing, was identified to be the mediator of this crosstalk. We also studied prostate stem cells and found this crosstalk in the TGFβ1-activated epithelial-mesenchymal transition (EMT). The crosstalk seemed to be a natural part of EMT. In summary, we identify a crosstalk between Akt phosphatases which is not present in non-transformed prostate cells but occurs in cancer cells and stem cells transformed by TGFβ-1. This crosstalk is important for cellular invasion.
Phosphatases regulate the Akt oncogene.
Crosstalk between Akt phosphatases in prostate cancer cells and in TGF-β1 activated stem cells but not in non-transformed cells.
This back-up mechanism facilitates invasive migration of prostate stem and cancer cells.
Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment.
Akt 激酶调节多种细胞过程，包括生长、增殖和存活，并且与肿瘤疾病相关。我们在这里报告几种 Akt 调节磷酸酶之间的串扰，这些磷酸酶控制 Akt 的激活形式（磷酸化）的水平，并影响肿瘤细胞的侵袭性。在前列腺癌细胞系中，我们观察到瞬时转染 PTEN 降低了内源性 PHLPPs 的水平，而相反，瞬时转染 PHLPPs 降低了内源性 PTEN 的水平。此外，siRNA 沉默 PTEN 导致 PHLPP 水平升高。这种现象在未转化细胞或前列腺干细胞中没有出现。这种串扰促进了癌细胞的侵袭，并受表观遗传调控过程的控制，其中涉及 miR（miR-190 和 miR214）、多梳蛋白组蛋白和 DNA 甲基化的激活。已显示嘌呤能 P2X4 受体在伤口愈合中起作用，被鉴定为这种串扰的介导物。我们还研究了前列腺干细胞，在 TGFβ1 激活的上皮-间充质转化（EMT）中发现了这种串扰。这种串扰似乎是 EMT 的自然组成部分。总之，我们鉴定了 Akt 磷酸酶之间的串扰，这种串扰在非转化的前列腺细胞中不存在，但在 TGFβ-1 转化的癌细胞和干细胞中存在。这种串扰对于细胞侵袭很重要。
磷酸酶调节 Akt 癌基因。
前列腺癌细胞和 TGF-β1 激活的干细胞中 Akt 磷酸酶之间的串扰，但在非转化细胞中不存在。
这种备份机制促进了前列腺干细胞和癌细胞的侵袭性迁移。
对 Akt 调节的表征可能导致对肿瘤发展的更好理解，并为治疗提供新策略。
