Progesterone receptor (PR) polyproline domain (PPD) mediates inhibition of epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer cells

Abstract

Recent evidence has suggested a possible role for progesterone receptor (PR) in the progression of non-small cell lung cancer (NSCLC). However, little is known concerning roles of PR in NSCLC. PR contains a polyproline domain (PPD), which directly binds to the SH3 domain of signaling molecules. Because PPD-SH3 interactions are essential for EGFR signaling, we hypothesized that the presence of PR-PPD interfered with EGFR-mediated signaling and cell proliferation. We examined the role of PR-PPD in cell proliferation and signaling by stably expressing PR-B, or PR-B with disrupting mutations in the PPD (PRBΔSH3), from a tetracycline-regulated promoter in A549 NSCLC cells. PR-B dose-dependently inhibited cell growth in the absence of ligand, and progestin (R5020) treatment further suppressed the growth. Treatment with RU486 abolished PR-B- and R5020-mediated inhibition of cell proliferation. Expression of PR-BΔSH3 and treatment with R5020 or RU486 had no effect on cell proliferation. Furthermore, PR-B expression but not PR-BΔSH3 expression reduced EGF-induced A549 proliferation and activation of ERK1/2, in the absence of ligand. Taken together, our data demonstrated the significance of PR extranuclear signaling through PPD interactions in EGFR-mediated proliferation and signaling in NSCLC.

Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer

“…However, a recent study also indicates that extranuclear PR actions can interfere or block growth-promoting signaling pathways. Expression of PR-B in NSCLC cells [77], independent of progestins, was shown to inhibit cell proliferation via PR-PPD mediated inhibition of the EGFR-mediated MAPK signaling pathway [77].…”

Triple SILAC identified progestin-independent and dependent PRA and PRB interacting partners in breast cancer

“…To identify PRA and PRB interacting partners, we applied a Tet-on lentiviral transduction technique to transduce PRA or PRB into T47DC42 (ER -, PR-) breast cancer cells, as previously described 20 , 28 . To check the expression of PRA and PRB, T47DC42-PRA and T47DC42-PRB 200,000 cells were plated in phenol red-free DMEM (Dulbecco’s modified eagle medium), 5% DCC-FBS (Dextran-coated charcoal-stripped FBS; Gibco/Life Technologies) and 1% penicillin/streptomycin (PenStrep) in a 6-well plate and incubated overnight.…”

Identification of Targets and Active Components of Yiqi SanJie Formula Against Lung Neoplasms Based on Network Pharmacology Analysis and Molecular Docking

“…48 Studies have shown the importance of PR through PPD interaction in EGFR-mediated NSCLC proliferation and signal transduction. 49 Therefore, endocrine regulation is predicted to be helpful in the treatment of lung cancer. PGHS2 can be induced to produce prostaglandins, which mediate responses to physiological stress such as infection and inflammation.…”