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 confrmed 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 effciency of injected human lung cancer cells into bone marrow, liver, and lungs in an immunodefcient 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 fnding, we propose that pituitary SexHs play a signifcant 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.