Increased endogenous PKG I activity attenuates EGF-induced proliferation and migration of epithelial ovarian cancer via the MAPK/ERK pathway.
Ting LanYing LiYue WangZhong-Cheng WangChun-Yan MuAi-Bin TaoJian-Li GongYuan ZhouHao XuShi-Bao LiBing GuPing MaLan LuoPublished in: Cell death & disease (2023)
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.
Keyphrases
- cell proliferation
- small cell lung cancer
- protein kinase
- pi k akt
- epidermal growth factor receptor
- signaling pathway
- tyrosine kinase
- high glucose
- diabetic rats
- cell cycle arrest
- mouse model
- induced apoptosis
- growth factor
- nitric oxide
- drug induced
- end stage renal disease
- gene expression
- chronic kidney disease
- oxidative stress
- newly diagnosed
- cell death
- inflammatory response
- bone marrow
- nuclear factor
- endoplasmic reticulum stress
- patient reported outcomes