title: Pituitary sex hormones enhance the pro‑metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase‑1.
abstract: We report that human lung cancer cell lines express functional receptors for pituitary sex hormones (SexHs) and respond to stimulation by follicle‑stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). Expression of these receptors has also been confirmed in patient lung cancer samples at the mRNA level. Stimulation of human lung cancer cell lines with FSH, LH, or PRL stimulated migration and chemotaxis, and some cell lines responded by enhanced proliferation. Moreover, priming of human lung cancer cells by exposing them to pituitary SexHs resulted in enhanced seeding efficiency of injected human lung cancer cells into bone marrow, liver, and lungs in an immunodeficient mouse model. The chemotaxis of lung cancer cell lines corresponded with the activity of heme oxygenase‑1 (HO‑1), as stimulation of these cells by FSH, LH, and PRL downregulated its expression in a p38 MAPK‑dependent manner. Moreover, while downregulation of HO‑1 by the small‑molecule inhibitor tin protoporphyrin (SnPP) promoted migration, upregulation of HO‑1 by the small‑molecule activator cobalt protoporphyrin (CoPP) showed the opposite effect. Based on this finding, we propose that pituitary SexHs play a significant role in the pathogenesis of lung cancer, particularly when the blood level of FSH increases due to gonadal dysfunction with advanced age. Finally, we propose that upregulation of HO‑1 expression by a small‑molecule activator may be effective in controlling SexH‑induced cell migration in lung cancer.
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelbaset-Ismail
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pedziwiatr
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Niklinski
authors.affiliation: Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Charkiewicz
authors.affiliation: Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Moniuszko
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Magda
authors.initials: M
authors.lastname: Kucia
authors.affiliation: Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002633:Chemotaxis / Q000187:drug effects*; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007986:Luteinizing Hormone / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D010902:Pituitary Gland / Q000378:metabolism; D011388:Prolactin / Q000008:administration & dosage / Q000378:metabolism; D011524:Protoporphyrins / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D011388:Prolactin; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases