Novel aspects of PGRMC1: Tumorigenesis promotion, EGFR stabilization and P450 activation in breast and lung cancer.

摘要

Tumorigenesis is a complex process composed of network of proteins which are disregulated. Thus, cancer patients are treated with a combination of drugs in attempts to inhibit growth and progression of cancer. In some cases patients develop resistance to drugs and in other cases the patients are non-responsive. Consequently, there are ongoing demands for new therapeutic targets. Pgrmc1 (p&barbelow;rogesterone r&barbelow;eceptor m&barbelow;embrane c&barbelow;omponent 1) is a heme binding protein and is upregulated in several types of cancer, including breast, lung, colon and ovarian cancer. High levels of Pgrmc1 in cancer is associated with DNA damage resistance, apoptotic suppression and chemotherapy resistance. Adding another novel action to Pgrmc1, we demonstrated that Pgrmc1 promotes proliferation, migration and metastasis phenotypes which are driven by receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR). In the present study we demonstrated that Pgrmc1 stabilizes EGFR at the plasma membrane as well as co-precipitates, co-fractionates and co-localizes with EGFR. Moreover, Pgrmc1 activates CYP19 and CYP3A4 which are important players in estrogen synthesis and xenobiotic metabolism respectively. Pgrmc1 phenotypes can be inhibited by a small molecule AG-205. Thus, targeting Pgrmc1 is a potential therapeutic in both EGFR- and estrogen-dependent cancer.;KEYWORDS: Pgrmc1, Tumorigenesis Promotion, EGFR Stabilization, P450 Activation