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.

A novel potential role of pituitary gonadotropins in the pathogenesis of human colorectal cancer

“…By contrast, modulation of the pituitary–gonad axis by means of estrogen administration was correlated with a decreased risk of certain gastrointestinal tumors [ 37 ]. In our previous reports we demonstrated the presence of functional SexH receptors in human lung cancer [ 16 ], rhabdomyosarcoma [ 21 ], and leukemia cells [ 22 ].…”

“…To address this issue, we focused our research on the effect of PtGs and studied, in addition to FSH, the effects of luteinizing hormone (LH) and prolactin (PRL) on colorectal cancer (CRC) cell lines. All of these PtGs are potent mitogens, and their role has already been associated with other human malignancies, including prostate [ 14 ], breast [ 15 ], lung [ 16 ], and ovarian cancer [ 17 ] as well as certain sarcomas [ 18 ].…”

“…Similarly, functional expression of FSH and LH receptors in established breast cancer cell lines has shown that sex hormones (SexHs) regulate breast cancer cell motility, adhesion, and invasion [ 20 ]. Moreover, functional receptors for pituitary gonadotropins and gonadal SexHs were identified on the surface of human lung cancer cells [ 16 ], rhabdomyosarcoma cells [ 21 ], and leukemia cells [ 22 ].…”

Heme oxygenase‐1 induction mediates chemoresistance of breast cancer cells to pharmorubicin by promoting autophagy via PI3K/Akt pathway

“…HO has 2 isozymes, heme oxygenase‐1 (HO‐1) and heme oxygenase‐2 (HO‐2), and HO‐1 is high inductivity under various chemical and physical cellular stresses. Given that HO‐1 has cytoprotective properties, it has attracted great attention on promoting tumour cell survival in many cancers as followings: increased expression of HO‐1 promoted primary and metastatic prostate tumour growth; Up‐regulating of HO‐1 expression might be effective in controlling cells migration in lung cancer; HO‐1 overexpression could mediate EGF‐induced colon cancer cell proliferation via PI3K/Akt signalling pathway . Furthermore, it was reported that the activation of Src/STAT3/HO‐1/autophagy signalling was supposed to play a crucial role in protecting breast cancer cells from doxorubicin‐induced cytotoxicity .…”

Novel evidence that pituitary sex hormones regulate migration, adhesion, and proliferation of embryonic stem cells and teratocarcinoma cells

“…Evidence has accumulated which revealed, that as potent mitogens, SexHs play an important role in the development and progression of cancers arising from tissues that are sensitive to SexH stimulation, such as the gonads, uterus, prostate, and breast (5–8). However, it has been recently demonstrated that both pituitary- and gonad-derived SexHs also play a role in the pathogenesis of other malignancies, such as lung cancer (9), rhabdomyosarcoma (10) and leukemia (11), and direct migration and adhesion of cells derived from these malignancies.…”