The role of progesterone receptor membrane component 1 (PGRMC1) in cytochromes P450 (CYP)- mediated drug metabolism and its Implication in chemotherapy resistance
Year: 2022
Type: dissertation
Abstract: Cytochrome P450s (CYPs) are of major importance in endobiotic and xenobiotic metabolism. Variability in CYP expression and activity between individuals and disease states leads to different metabolic phenotypes. Variation in the metabolic phenotype of microsomal CYPs may also be caused by differential interaction with other proteins, such as their obligatory electron supplier, cytochrome P450 oxidoreductase (CPR), cytochrome b5 (cyt b5) and progesterone receptor membrane component 1 (PGRMC1). PGRMC1 contains a cyt b5-like haem-binding region that enables PGRMC1 dimerization through hydrophobic haem-haem stacking. This dimerization was first deemed as necessary for the interaction of PGRMC1 with CYPs and the epidermal growth factor receptor (EGFR). These interactions have been suggested to play a role in CYP-mediated metabolism, cancer cell chemoresistance and cancer proliferation. PGRMC1 overexpression in several cancers, including breast cancer (BC), makes it a potential therapeutic target and demands a better characterization of its structure, function and binding partners. Previous work developed at our lab using an in-house developed bacterial cell model that allows co-expression of human CYPs, PGRMC1 and CPR evidenced that PGRMC1’s effect on CYP’s activity is not only isoform dependent but also substrate-dependent. To extend our findings to more human-like conditions, breast cancer cell lines were used, either sensitive (MCF-7) or resistant to doxorubicin (DOX) (MCF-7-resistant and KCR), to assess the role of PGRMC1 expression in DOX resistance and its effect on the CYP complex. The expression of genes involved in xeno- and endobiotic metabolism in cells that acquired DOX-resistance was studied. No significant differences were found in the expression profiles of PGRMC1 mRNA between DOX-resistant and non-resistant MCF-7 cells. Nevertheless, the results suggest a role of arachidonic and retinoid acid metabolic pathways in early resistance to DOX in BC. Although expressing relative low levels of xenobiotic CYPs (mRNA), BC cells were shown to be metabolically competent in drug metabolism.
Author: Barata, Isabel Sousa
Language: Portuguese
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7005702737