PGRMC1 Elevation in Multiple Cancers and Essential Role in Stem Cell Survival

Abstract

Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytoch-rome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.

Identification of PGRMC1 as a Candidate Oncogene for Head and Neck Cancers and Its Involvement in Metabolic Activities

“…Previous studies have shown PGRMC1 is induced in many different types of cancers, including breast, thyroid, colon, ovary, and lung cancers (Hampton et al, 2015), and required for the key functions of tumor growth, cancer cell survival, and motility, particularly after chemotherapeutic drugs (Cahill et al, 2016). PGRMC1 originally was identified by expression induction during carcinogenesis in liver cancer (Nie et al, 2006), and recently was observed its elevation with tumor stage in ovarian cancer and estrogen receptor-negative breast cancer (Neubauer et al, 2008).…”

“…The association of smoking and HNSC was observed in developing countries, while the human papillomavirus (HPV) as a critical role affecting nonsmokers in the rise of HNSCC is emerging in developed countries (Begum and Westra, 2008;Desrichard et al, 2018). Recent studies revealed that the expression of PGRMC1 dramatically elevated in head and neck cancer (Hampton et al, 2015). However, to our knowledge, the oncogenic role of the PGRMC1 gene in head and neck cancer has not been systematically analyzed, and additional researches are merited.…”

The evolutionary appearance of signaling motifs in PGRMC1

“…S2R activity is vitally important for many cancer cells (39), and is associated with cancer stem cell properties related to proliferative status and survival (47)(48)(49). It is conceivable that this PGRMC1-S2R system, that regulates differentiation, proliferative, and survival decisions, reflects a remnant of the ancestral control of replication of the primitive single celled eukaryote.…”

High Level of Progesteron Receptor Membrane Component 1 (PGRMC 1) in Tissue of Breast Cancer Patients is Associated with Worse Response to Anthracycline-Based Neoadjuvant Therapy

“…Such a target could be represented by progesterone receptor membrane component 1 (PGRMC1). PGRMC1 protein and mRNA was shown to be upregulated in various tumors, including colon, lung, ovary, cervix and breast, suggesting a role of the receptor in cancer pathology [9][10][11][12][13][14]. In breast cancer, the expression of PGRMC1 further correlates with metastasis of lymph nodes, larger tumor size, poorer overall-and tumor-free survival [12,14,15].…”

“…PGRMC1 protein and mRNA was shown to be upregulated in various tumors, including colon, lung, ovary, cervix and breast, suggesting a role of the receptor in cancer pathology [9][10][11][12][13][14]. In breast cancer, the expression of PGRMC1 further correlates with metastasis of lymph nodes, larger tumor size, poorer overall-and tumor-free survival [12,14,15]. Further, PGRMC1 was shown to be associated with resistance to the chemotherapeutic agent doxorubicin by promoting its degradation via cytochrome P450 enzymes and resistance to treatment with cisplatin and paclitaxel [16][17][18][19][20].…”