title: Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients.
abstract: Cancer is one of the leading causes of death, and there is an urgent need for new biomarkers and therapeutic targets. The progesterone receptor membrane component 1 (Pgrmc1) protein is upregulated in multiple types of cancer, and Pgrmc1 is required for tumor cell proliferation, motility and tumor formation in vivo. Furthermore, a small molecule inhibitor of Pgrmc1 suppressed the growth of lung, breast and cervical cancer cell lines. Recently, Pgrmc1 was identified as the sigma-2 receptor, a putative type of opioid receptor, and sigma-2 receptors are induced in cancers. However, Pgrmc1 shares no homology with known opioid or hormone receptors but is related to cytochrome b(5), and Pgrmc1 binds to heme and has reducing activity. In this study, we have analyzed Pgrmc1 levels in clinical tumor samples from squamous cell lung cancers (SCLC) and lung adenocarcinomas compared to corresponding nonmalignant tissue. Pgrmc1 levels increased significantly (p ≤ 0.05) in 12/15 SCLC samples and was elevated in poorly differentiated tumors. Pgrmc1 was highly expressed in SCLC cell lines, and SCLC cell survival was inhibited by siRNA knockdown of Pgrmc1 or the Pgrmc1 inhibitor AG-205. In adenocarcinomas, 6/15 tumors significantly had elevated Pgrmc1 levels, which correlated with patient survival. Pgrmc1 localizes to secretory vesicles in cancer cells, and Pgrmc1 was secreted by lung cancer cells. Furthermore, Pgrmc1 was significantly elevated in the plasma of lung cancer patients compared to noncancer patients. Together, the results demonstrate that Pgrmc1 is a potential tumor and serum biomarker, as well as a therapeutic target, for lung cancer.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Shakeel U R
authors.initials: SU
authors.lastname: Mir
authors.forename: Ikhlas S A
authors.initials: IS
authors.lastname: Ahmed
authors.forename: Susanne
authors.initials: S
authors.lastname: Arnold
authors.forename: Rolf J
authors.initials: RJ
authors.lastname: Craven
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000097:blood / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D017480:Receptors, sigma / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D017480:Receptors, sigma; C106107:sigma-2 receptor