Pgrmc1 (Progesterone Receptor Membrane Component 1) Associates with Epidermal Growth Factor Receptor and Regulates Erlotinib Sensitivity

Abstract

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and metabolism. Epidermal growth factor receptor (EGFR) is a transmembrane receptor-tyrosine kinase that is associated with cancer progression, and the EGFR inhibitors erlotinib/tarceva and tyrphostin/AG-1478 are potent anti-cancer therapeutics. Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b 5 -related protein that is up-regulated in tumors and promotes cancer growth. Pgrmc1 and its homologues have been implicated in cell signaling, and we show here that Pgrmc1 increases susceptibility to AG-1478 and erlotinib, increases plasma membrane EGFR levels, and co-precipitates with EGFR. Pgrmc1 co-localizes with EGFR in cytoplasmic vesicles and cofractionates with EGFR in high density microsomes. The findings have therapeutic potential because a Pgrmc1 small molecule ligand, which inhibits growth in a variety of cancer cell types, de-stabilized EGFR in multiple tumor cell lines. EGFR is one of the most potent receptor-tyrosine kinases driving tumorigenesis, and our data support a role for Pgrmc1 in promoting several cancer phenotypes at least in part by binding EGFR and stabilizing plasma membrane pools of the receptor.The proliferation of a number of cancers is driven by receptor-tyrosine kinases, which span the cell membrane and transmit signals from polypeptide hormones. Activation of the epidermal growth factor receptor (EGFR) 2 -tyrosine kinase has been linked to increased proliferation, angiogenesis, metastasis, and decreased apoptosis (1). EGFR is up-regulated in a variety of tumors (2), and EGFR and HER2/neu overexpression are associated with a poor prognosis in multiple tumor types (3). EGFR is inhibited by a growing number of drugs, including antibodies such as cetuximab and small molecule inhibitors such as erlotinib (Tarceva/OSI-774) and gefitinib (3, 4). However, the degree to which patients respond favorably to these drugs varies markedly between those expressing wild-type EGFR and mutants (5-7). One of the emerging themes in targeting kinases is the importance of processing events, intracellular transport, and interaction partners among the kinases (8,9). In the present study we demonstrate an association between EGFR and progesterone receptor membrane component 1 (Pgrmc1).Pgrmc1 is related to cytochrome b 5 and has binding sites for Src homology 2 (SH2) and SH3 domain-containing proteins and consensus phosphorylation sites for tyrosine kinases (10). Pgrmc1 is induced in a variety of cancers, including breast, thyroid, colon, ovary, and lung cancer (11-16). Furthermore, Pgrmc1 expression increases with tumor stage in ovarian cancer (11), and Pgrmc1 is elevated in estrogen receptor-negative breast tumors (17, 18). Pgrmc1 was originally identified by its induction by dioxin during liver tumorigenesis (19) and is one of six genes in a signature predicting non-genotoxic carcinogens (20). Pgrmc1 is required for key functions in tumor growth, promoting survival in cancer cells...

Role of Pgrmc1 in estrogen maintenance of meiotic arrest in zebrafish oocytes through Gper/Egfr

“…Results of subsequent studies have indicated that AG205 binds to PGRMC1 and has a similar effect to that observed after treatment with Pgmrc1 siRNA in lung cancer cells, decreasing phosphorylation of ERK (Ahmed et al 2010b). Treatment with AG205 also decreases EGFR-dependent signaling in lung cancer cells, consistent with the proposed role of PGRMC1 as a binding partner with EGFR (Ahmed et al 2010a). Thus, AG205 is a useful PGRMC1 antagonist for exploring its adaptor protein functions.…”

“…Results from a recent study by Thomas et al (2014) indicating that PGRMC1 co-immunoprecipitates with membrane progesterone receptor alpha (mPRa) in several breast cancer cell lines and enhances its expression and function on the plasma membrane, and also enhances the membrane expression of estrogen receptor beta (ERb), further support a role of PGRMC1 as an adaptor protein and suggests that it has an important function in regulating the cell-surface expression and membrane receptor functions of steroid receptors. Results described in a recent report by Ahmed et al (2010a) which revealed that PGRMC1 associates with epidermal growth factor receptor (EGFR) and maintains EGFR at the plasma membrane indicate that PGRMC1 also acts as an adaptor protein for EGFR. This finding is likely to have broad implications for tumorigenesis because over-expression of EGFR in cancer cells is highly correlated with malignancy (Ono & Kuwano 2006).…”

Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

“…Notably, PGRMC1 has been shown to interact with EGFR and increase plasma membrane EGFR levels. 70 Accordingly, PGRMC1 expression increases in vitro breast cancer cell proliferation in the presence of growth factors and medroxyprogesterone acetate. 17 A link between PGRMC1 and EGFR has also been identified in zebrafish oocytes as a component of estrogen-induced meiotic arrest.…”

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

“…PGRMC1 has been shown to function as an adaptor protein for mPR␣, closely associating with it and regulating its expression and functions on the cell membrane (64). PGRMC1 likely influences multiple receptor functions in HUVECs because it also regulates the expression of EGFR and ER␤ on the membranes of human cells (1,64). Finally, the fact that coincubation with a nuclear estrogen receptor antagonist, ICI 182,780, did not modulate the NO response to the progestin treatments suggests that their effects are not mediated through a nuclear estrogen receptor-dependent pathway.…”