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

Rolf J Craven,Rachel Stewart,Dana Napier,Pier Paolo Claudio,Kaia K Hampton

doi:10.4236/alc.2015.43006

Rolf J Craven, Rachel Stewart + Show 3 more

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https://doi.org/10.4236/alc.2015.43006

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Journal: Advances in lung cancer (Irvine)	Publication Date: Jan 1, 2015
Citations: 29	License type: CC BY 4.0

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.

Highlights

progesterone receptor membrane component 1 (PGRMC1) is induced in a number of cancer types [1], including breast, ovarian and lung cancers, and a small study indicated that PGRMC1 is associated with poor survival in lung adenocarcinoma [2]
PGRMC1 is essential for lung tumor formation and metastasis, so we determined PGRMC1 levels by immunohistochemistry in 330 lung cancer samples using tissue microarrays, which included 58 patients with survival data
In staining of a tissue from an earlier study, we found that recombinant PGRMC1 fusion protein blocked staining with the antibody, suggesting that it is specific (Figure 1(a) and Figure 1(b))

Summary

Introduction

PGRMC1 is induced in a number of cancer types [1], including breast, ovarian and lung cancers, and a small study indicated that PGRMC1 is associated with poor survival in lung adenocarcinoma [2]. PGRMC1 is expressed in sebaceous carcinomas [3]. PGRMC1 plays a causative role in cancer progression, because in vitro, PGRMC1 increases tumor cell proliferation, chemotherapy resistance and invasion, and in vivo, PGRMC1 increases tumor growth, angiogenesis and metastasis [4]-[9]. There are a number of potential mechanisms through which PGRMC1 might promote tumor growth. PGRMC1 associates with the epidermal growth factor receptor (EGFR) and regulates susceptibility to the EGFR inhibitor erlotinib by increasing plasma membrane pools of EGFR [10]. PGRMC1 increases EGFR levels in Zebrafish [11]. The EGFR-PGRMC1 complex drives invasion, at least in part, by activating matrix metalloproteinases [12]

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