Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule
| Autor: | Ikhlas S.A. Ahmed, Marlene N. Mattingly, Rolf J. Craven, Katherine E. Twist, Hannah J. Rohe |
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| Rok vydání: | 2010 |
| Předmět: |
Lung Neoplasms
Mice Nude Breast Neoplasms Heme Biology medicine.disease_cause Mice Carcinoma Non-Small-Cell Lung Cell Line Tumor Neoplasms Progesterone receptor medicine Animals Humans Lung cancer PGRMC1 Carcinogen Cell Proliferation Pharmacology Membrane Proteins Neoplasms Experimental medicine.disease Molecular biology Protein Structure Tertiary Sterol regulatory element-binding protein Cell biology Cholesterol Apoptosis Cell culture Molecular Medicine Female Cell Migration Assays Receptors Progesterone Carcinogenesis Neoplasm Transplantation |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 333:564-573 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.109.164210 |
| Popis: | Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b5, binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulin-induced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1-knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer. |
| Databáze: | OpenAIRE |
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