Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
School of Medical Technology, Xuzhou Medical University, Xuzhou City, Jiangsu Province, China.
Cell Death Dis. 2023 Jan 19;14(1):39. doi: 10.1038/s41419-023-05580-y.
The type I cGMP-dependent protein kinase (PKG I) is recognized as a tumor suppressor, but its role in EGFR regulated epithelial ovarian cancer (EOC) progression remains unclear. We evaluated the in vivo and in vitro effects of activated PKG I in EGF-induced EOC cell proliferation, migration, and invasion. The expressions of EGFR and PKG I were elevated, but the activated PKG I was decreased in EOC tissues of patients and cells lines. The addition of 8-Br-cGMP, a specific PKG I activator, attenuated the EGF-induced EOC cell proliferation, migration, and invasion in vitro. Similarly, activated PKG I also attenuated EOC progression in vivo using an EOC xenograft nude mouse model. The activated PKG I interacted with EGFR, causing increased threonine (693) phosphorylation and decreased tyrosine (1068) phosphorylation of EGFR, which resulted in disrupted EGFR-SOS1-Grb2 combination. Subsequently, the cytoplasmic phosphorylation of downstream proteins (c-Raf, MEK1/2, and ERK1/2) were declined, impeding the phosphorylated ERK1/2's nucleus translocation, and this reduction of phosphorylated tyrosine (1068) EGFR and ERK1/2 were also abolished by Rp-8-Br-cGMPS. Our results suggest that the activation of PKG I attenuates EGF-induced EOC progression, and the 8-Br-cGMP-PKG I-EGFR/MEK/ERK axis might be a potential target for EOC therapy.
I 型 cGMP 依赖性蛋白激酶（PKG I）被认为是一种肿瘤抑制因子，但它在表皮生长因子受体（EGFR）调节的卵巢上皮性癌（EOC）进展中的作用尚不清楚。我们评估了激活的 PKG I 在 EGF 诱导的 EOC 细胞增殖、迁移和侵袭中的体内和体外作用。EGFR 和 PKG I 的表达升高，但 EOC 组织和细胞系中激活的 PKG I 减少。特定的 PKG I 激活剂 8-Br-cGMP 的添加可减弱 EGF 诱导的 EOC 细胞在体外的增殖、迁移和侵袭。同样，使用 EOC 异种移植裸鼠模型，激活的 PKG I 也可减弱体内 EOC 的进展。激活的 PKG I 与 EGFR 相互作用，导致 EGFR 的苏氨酸（693）磷酸化增加和酪氨酸（1068）磷酸化减少，从而破坏 EGFR-SOS1-Grb2 结合。随后，下游蛋白（c-Raf、MEK1/2 和 ERK1/2）的细胞质磷酸化减少，阻碍磷酸化 ERK1/2 的核转位，这种磷酸化酪氨酸（1068）EGFR 和 ERK1/2 的减少也被 Rp-8-Br-cGMPS 所消除。我们的结果表明，PKG I 的激活可减弱 EGF 诱导的 EOC 进展，8-Br-cGMP-PKG I-EGFR/MEK/ERK 轴可能是 EOC 治疗的潜在靶点。
