Progesterone Receptor Membrane Component (PGRMC)1 and PGRMC2 and Their Roles in Ovarian and Endometrial Cancer

Abstract

Cancers of the female reproductive tract are both lethal and highly prevalent. For example, the five-year survival rate of women diagnosed with ovarian cancer is still less than 50%, and endometrial cancer is the fourth most common cancer in women with > 65,000 new cases in the United States in 2020. Among the many genes already established as key participants in ovarian and endometrial oncogenesis, progesterone receptor membrane component (PGRMC)1 and PGRMC2 have gained recent attention given that there is now solid correlative information supporting a role for at least PGRMC1 in enhancing tumor growth and chemoresistance. The expression of PGRMC1 is significantly increased in both ovarian and endometrial cancers, similar to that reported in other cancer types. Xenograft studies using human ovarian and endometrial cancer cell lines in immunocompromised mice demonstrate that reduced expression of PGRMC1 results in tumors that grow substantially slower. While the molecular underpinnings of PGRMCs’ mechanisms of action are not clearly established, it is known that PGRMCs regulate survival pathways that attenuate stress-induced cell death. The objective of this review is to provide an overview of what is known about the roles that PGRMC1 and PGRMC2 play in ovarian and endometrial cancers, particularly as related to the mechanisms through which they regulate mitosis, apoptosis, chemoresistance, and cell migration.

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

“…Peluso and Pru [181] report that PGRMC1 associates with eukaryotic ribosomal translation initiation factors. In a pilot co-IP and proteomic protein identification experiment, Sarah Teakel in the author's lab had also identified ribosomal proteins in the co-IP pellets using HA-tagged PGRMC1 as bait.…”

“…We also already had the proteomics pathways analysis that was later published in 2020 [50], suggesting that PGRMC1 phosphorylation status could affect the abundance of some proteins involved in translation, but also that the dramatic changes in protein abundance profiles that we observed could be due to alterations in the subset of cellular mRNAs being translated. That prompted the author to investigate hints of ribosomal association from published resources, where The Human Protein Atlas reported prominent localization of PGRMC1 to the nucleolus, the site of ribosome biogenesis, and speculate that PGRMC1 "may affect the composition of ribosomes, translation initiation factors" [47], as cited by Peluso and Pru [181]. Terzaghi et al [182] later reported the nucleolar localization (i.e., the site of ribosomal RNA synthesis and pre-ribosomal particle assembly [183]) of PGRMC1 in bovine granulosa cells and oocytes.…”

“…However, the possibility that PGRMC1 can affect protein expression at the translational level gains credence from the report of Peluso and Pru. Like our lab, they had also been investigating PGRMC1-ribosomal interactions prior to 2016, and they recently reported the presence of several ribosomal elongation initiation factors in PGRMC1and PGRMC1 co-IP pellets [181]. To consider just one example, for PGRMC1 these included the Eukaryotic Initiation Factor 3 (EIF3) subunit EIF3B.…”

Rapid Actions of the Nuclear Progesterone Receptor through cSrc in Cancer

“…Although the PR is primarily known for its function as a ligand-activated transcription factor, its interaction with P4 also triggers rapid or transcription-independent effects. Immediate effects mainly occur through the activation of mPRs [ 6 ] and PGRMCs [ 7 , 8 , 9 ], whereas nuclear actions are exerted by the PR [ 10 ], but the latter is the only one that can exert both effects. In addition to the domains involved in its function as a transcription factor, the PR possesses a polyproline-rich (PXPP) motif between aa 421 and 428 that binds to the SH3 domains of several cytoplasmic molecules, including cSrc ( Figure 1 ), hematopoietic cell kinase (HCK), Fyn, and other kinases or adapter proteins such as the regulatory subunit of PI3K (p85), CRK proto-oncogene adaptor protein (Crk), and growth factor receptor-bound protein 2 (Grb2) [ 11 ].…”

Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division

“…The primary goal of this review article is to highlight the current knowledge of PGRMC1 function in regulating mammalian cell proliferation, specifically by mechanisms set in motion during the progression of cell division (M phase/cytokinesis), which, so far, has received less attention from the scientific community. Although PGRMC1, together with its partner PGRMC2, participates in many other functions that impact cell proliferation, such as cell viability and apoptosis and entry into the cell cycle, these functions have been reviewed elsewhere and will not be further discussed here [ 3 , 4 , 5 ].…”