Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

Xie,Mingxuan; You,Shaojin; Chen,Qiong; Chen,Xi; Hu,Chengping

doi:10.3892/or.2013.2336

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

Authors:
- Mingxuan Xie
- Shaojin You
- Qiong Chen
- Xi Chen
- Chengping Hu
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Affiliations: Department of Gerontology and Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China, Histopathology Core, Atlanta Research and Educational Foundation/Atlanta VA Medical Center, Decatur, GA, USA
Published online on: March 6, 2013 https://doi.org/10.3892/or.2013.2336
Pages: 1873-1880

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Abstract

Lung cancer is the leading cause of cancer morbidity and mortality in the world. The incidence of lung cancer, particularly lung adenocarcinoma, is increasing in women compared to men. The role of sex hormones in the development of lung cancer has attracted substantial interest, but remains largely unknown. In this study, we demonstrated that membrane progesterone receptor α (mPRα) was expressed in a lung adenocarcinoma cell line, A549, and was located on the cell membrane. In additional experiments, we found that mPRα functioned as an essential mediator for progesterone (P4)-induced inhibitory effects on cell migration and invasion of A549 cells. Furthermore, PP1 (an Src pathway inhibitor), when co-incubated with P4, synchronously enhanced the inhibitory effects of P4 on cell migration and invasion. To explore the mechanisms of inhibition, we found that P4 and PP1 induced a cascade of molecular signaling events, such as dephosphorylation of focal adhesion kinase (FAK) and downregulation of matrix metalloproteinase 9 (MMP-9). Our study provides a mechanistic view on the effects of P4 through mPRα→Src/FAK relevant pathways in human lung adenocarcinoma cells and may aid in the development of novel therapeutic tools for the treatment of lung cancer.

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1	Yang M and Pyo MY: Molecular epidemiology of lung cancer in female passive smokers. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 23:75–97. 2005. View Article : Google Scholar : PubMed/NCBI
2	Stabile LP, Davis AL, Gubish CT, et al: Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res. 62:2141–2150. 2002.PubMed/NCBI
3	Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S and Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 93:5925–5930. 1996. View Article : Google Scholar : PubMed/NCBI
4	Clarke CL and Sutherland RL: Progestin regulation of cellular proliferation. Endocr Rev. 11:266–301. 1990. View Article : Google Scholar : PubMed/NCBI
5	Lee WS, Harder JA, Yoshizumi M, Lee ME and Haber E: Progesterone inhibits arterial smooth muscle cell proliferation. Nat Med. 3:1005–1008. 1997. View Article : Google Scholar : PubMed/NCBI
6	Groshong SD, Owen GI, Grimison B, et al: Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Mol Endocrinol. 11:1593–1607. 1997. View Article : Google Scholar : PubMed/NCBI
7	Musgrove EA, Hunter LJ, Lee CS, Swarbrick A, Hui R and Sutherland RL: Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27(Kip1) association with cyclin E-Cdk2. J Biol Chem. 276:47675–47683. 2001. View Article : Google Scholar : PubMed/NCBI
8	Santen RJ, Manni A, Harvey H and Redmond C: Endocrine treatment of breast cancer in women. Endocr Rev. 11:221–265. 1990. View Article : Google Scholar : PubMed/NCBI
9	Thigpen JT, Brady MF, Alvarez RD, et al: Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol. 17:1736–1744. 1999.PubMed/NCBI
10	Lee YT: Better prognosis of many cancers in female: a phenomenon not explained by study of steroid receptors. J Surg Oncol. 25:255–262. 1984. View Article : Google Scholar : PubMed/NCBI
11	Su JM, Hsu HK, Chang H, et al: Expression of estrogen and progesterone receptors in non-small-cell lung cancer: immunohistochemical study. Anticancer Res. 16:3803–3806. 1996.PubMed/NCBI
12	Check JH, Sansoucie L, Chern J and Dix E: Mifepristone treatment improves length and quality of survival of mice with spontaneous lung cancer. Anticancer Res. 30:119–122. 2010.PubMed/NCBI
13	Marquez-Garban DC, Mah V, Alavi M, et al: Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer. Steroids. 76:910–920. 2011.PubMed/NCBI
14	Tiutiunova AM, Chirvina ED, Mironenko TV, Kartashov SZ and Luntovskaia VA: Hormonal balance in women with lung cancer and its changes after combined treatment. Vopr Onkol. 32:26–30. 1986.(In Russian).
15	Zhu Y, Rice CD, Pang Y, Pace M and Thomas P: Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA. 100:2231–2236. 2003. View Article : Google Scholar : PubMed/NCBI
16	Zhu Y, Bond J and Thomas P: Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA. 100:2237–2242. 2003. View Article : Google Scholar
17	Thomas P: Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol. 29:292–312. 2008. View Article : Google Scholar
18	Zuo L, Li W and You S: Progesterone reverses the mesenchymal phenotypes of basal phenotype breast cancer cells via a membrane progesterone receptor mediated pathway. Breast Cancer Res. 12:R342010. View Article : Google Scholar
19	Dosiou C, Hamilton AE, Pang Y, et al: Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol. 196:67–77. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ciavatta VT, Kim M, Wong P, et al: Retinal expression of Fgf2 in RCS rats with subretinal microphotodiode array. Invest Ophthalmol Vis Sci. 50:4523–4530. 2009. View Article : Google Scholar : PubMed/NCBI
21	Dhanesuan N, Sharp JA, Blick T, Price JT and Thompson EW: Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition. Breast Cancer Res Treat. 75:73–85. 2002. View Article : Google Scholar
22	Desai B, Ma T and Chellaiah MA: Invadopodia and matrix degradation, a new property of prostate cancer cells during migration and invasion. J Biol Chem. 283:13856–13866. 2008. View Article : Google Scholar : PubMed/NCBI
23	Beattie CW, Hansen NW and Thomas PA: Steroid receptors in human lung cancer. Cancer Res. 45:4206–4214. 1985.PubMed/NCBI
24	Wu CT, Chang YL, Shih JY and Lee YC: The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J Thorac Cardiovasc Surg. 130:979–986. 2005. View Article : Google Scholar : PubMed/NCBI
25	Fasco MJ, Hurteau GJ and Spivack SD: Gender-dependent expression of alpha and beta estrogen receptors in human nontumor and tumor lung tissue. Mol Cell Endocrinol. 188:125–140. 2002. View Article : Google Scholar : PubMed/NCBI
26	Kaiser U, Hofmann J, Schilli M, et al: Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer. Int J Cancer. 67:357–364. 1996. View Article : Google Scholar : PubMed/NCBI
27	Thomas P, Pang Y, Dong J, et al: Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinology. 148:705–718. 2007. View Article : Google Scholar
28	Pang Y and Thomas P: Progesterone signals through membrane progesterone receptors (mPRs) in MDA-MB-468 and mPR-transfected MDA-MB-231 breast cancer cells which lack full-length and N-terminally truncated isoforms of the nuclear progesterone receptor. Steroids. 76:921–928. 2011.
29	Krietsch T, Fernandes MS, Kero J, et al: Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. Mol Endocrinol. 20:3146–3164. 2006. View Article : Google Scholar
30	Foster H, Reynolds A, Stenbeck G, Dong J, Thomas P and Karteris E: Internalisation of membrane progesterone receptor-alpha after treatment with progesterone: Potential involvement of a clathrin-dependent pathway. Mol Med Rep. 3:27–35. 2010.
31	Schafer C, Born S, Mohl C, et al: The key feature for early migratory processes: dependence of adhesion, actin bundles, force generation and transmission on filopodia. Cell Adh Migr. 4:215–225. 2010. View Article : Google Scholar : PubMed/NCBI
32	Ishibashi H, Suzuki T, Suzuki S, et al: Progesterone receptor in non-small cell lung cancer - a potent prognostic factor and possible target for endocrine therapy. Cancer Res. 65:6450–6458. 2005. View Article : Google Scholar : PubMed/NCBI
33	Zhu Y, Hanna RN, Schaaf MJ, Spaink HP and Thomas P: Candidates for membrane progestin receptors - past approaches and future challenges. Comp Biochem Physiol C Toxicol Pharmacol. 148:381–389. 2008. View Article : Google Scholar : PubMed/NCBI
34	Losel RM, Besong D, Peluso JJ and Wehling M: Progesterone receptor membrane component 1 - many tasks for a versatile protein. Steroids. 73:929–934. 2008. View Article : Google Scholar : PubMed/NCBI
35	Guarino M: Src signaling in cancer invasion. J Cell Physiol. 223:14–26. 2010.
36	Hanke JH, Gardner JP, Dow RL, et al: Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem. 271:695–701. 1996. View Article : Google Scholar : PubMed/NCBI
37	Karni R, Mizrachi S, Reiss-Sklan E, Gazit A, Livnah O and Levitzki A: The pp60c-Src inhibitor PP1 is non-competitive against ATP. FEBS Lett. 537:47–52. 2003. View Article : Google Scholar : PubMed/NCBI
38	Finn RS, Bengala C, Ibrahim N, et al: Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 17:6905–6913. 2011. View Article : Google Scholar : PubMed/NCBI
39	Tryfonopoulos D, Walsh S, Collins DM, et al: Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol. 22:2234–2240. 2011. View Article : Google Scholar : PubMed/NCBI
40	Mitra SK, Hanson DA and Schlaepfer DD: Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 6:56–68. 2005. View Article : Google Scholar : PubMed/NCBI
41	Owens LV, Xu L, Craven RJ, et al: Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res. 55:2752–2755. 1995.PubMed/NCBI
42	Siesser PM and Hanks SK: The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res. 12:3233–3237. 2006. View Article : Google Scholar : PubMed/NCBI
43	Hsu SP, Chen TH, Chou YP, et al: Extra-nuclear activation of progesterone receptor in regulating arterial smooth muscle cell migration. Atherosclerosis. 217:83–89. 2011. View Article : Google Scholar : PubMed/NCBI
44	Herbst RS, Yano S, Kuniyasu H, et al: Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. Clin Cancer Res. 6:790–797. 2000.PubMed/NCBI
45	Martinella-Catusse C, Nawrocki B, Gilles C, Birembaut P and Polette M: Matrix-metalloproteinases in bronchopulmonary carcinomas. Histol Histopathol. 14:839–843. 1999.PubMed/NCBI
46	Aleshin A and Finn RS: SRC: a century of science brought to the clinic. Neoplasia. 12:599–607. 2010.PubMed/NCBI
47	Hung WC, Tseng WL, Shiea J and Chang HC: Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 288:156–161. 2010. View Article : Google Scholar : PubMed/NCBI
48	Xu XM, Zhang Y, Qu D, Feng XW, Chen Y and Zhao L: Osthole suppresses migration and invasion of A549 human lung cancer cells through inhibition of matrix metalloproteinase-2 and matrix metallopeptidase-9 in vitro. Mol Med Report. 6:1018–1022. 2012.PubMed/NCBI