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Aromatase-induced endogenous estrogen promotes tumour metastasis through estrogen receptor-α/matrix metalloproteinase 12 axis activation in castration-resistant prostate cancer.
Cancer Lett 2019; 467:72-84CL

Abstract

Castration-resistant prostate cancer (CRPC) following androgen deprivation therapy remains a major obstacle advanced prostate cancer management. Aromatase catalyzes estrogen from androgens, yet the role of aromatase-generated endogenous estrogen in CRPC is poorly understood. In this study, we assessed the expression and function of aromatase in CRPC. We found that aromatase expression was significantly increased in CRPC tissues and cell lines. In some prostate cancer cell lines, aromatase was predominantly expressed in CD44+ subsets. Bicalutamide treatment significantly increased aromatase expression, and CYP19A1 expression positively correlated with estrogen responses and epithelial-mesenchymal transition. Aromatase knockdown in PC3 cells reduced invasiveness and decreased metastasis-related gene expression. The aromatase inhibitor, letrozole, attenuated tumour metastasis in castrated PC3-xenograft mice. Mechanistically, aromatase-induced endogenous estrogen promoted estrogen receptor-α (ERα) binding to matrix metalloproteinase 12 (MMP12) promoter estrogen response element (ERE). MMP12 co-localized with CD44 on the cell membrane and MMP12 knockdown significantly reduced estradiol-induced PC3 invasion. Taken together, our findings indicated that increased endogenous estrogen, catalysed by elevated aromatase levels, enhanced MMP12 expression via ERα, participated in CRPC progression and promoted tumour metastasis. Thus, aromatase represents a potential novel therapeutic target for CRPC.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Shanghai First People's Hospital Shanghai Jiaotong University, Shanghai, 200080, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China. Electronic address: shijd@nankai.edu.cn.Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin, 300071, China. Electronic address: zhangju@nankai.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31499120

Citation

Liang, Zhixian, et al. "Aromatase-induced Endogenous Estrogen Promotes Tumour Metastasis Through Estrogen Receptor-α/matrix Metalloproteinase 12 Axis Activation in Castration-resistant Prostate Cancer." Cancer Letters, vol. 467, 2019, pp. 72-84.
Liang Z, Cao J, Tian L, et al. Aromatase-induced endogenous estrogen promotes tumour metastasis through estrogen receptor-α/matrix metalloproteinase 12 axis activation in castration-resistant prostate cancer. Cancer Lett. 2019;467:72-84.
Liang, Z., Cao, J., Tian, L., Shen, Y., Yang, X., Lin, Q., ... Zhang, J. (2019). Aromatase-induced endogenous estrogen promotes tumour metastasis through estrogen receptor-α/matrix metalloproteinase 12 axis activation in castration-resistant prostate cancer. Cancer Letters, 467, pp. 72-84. doi:10.1016/j.canlet.2019.09.001.
Liang Z, et al. Aromatase-induced Endogenous Estrogen Promotes Tumour Metastasis Through Estrogen Receptor-α/matrix Metalloproteinase 12 Axis Activation in Castration-resistant Prostate Cancer. Cancer Lett. 2019 Dec 28;467:72-84. PubMed PMID: 31499120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aromatase-induced endogenous estrogen promotes tumour metastasis through estrogen receptor-α/matrix metalloproteinase 12 axis activation in castration-resistant prostate cancer. AU - Liang,Zhixian, AU - Cao,Jiasong, AU - Tian,Lei, AU - Shen,Yongmei, AU - Yang,Xu, AU - Lin,Qimei, AU - Zhang,Ran, AU - Liu,Haitao, AU - Du,Xiaoling, AU - Shi,Jiandang, AU - Zhang,Ju, Y1 - 2019/09/06/ PY - 2019/06/30/received PY - 2019/08/17/revised PY - 2019/09/04/accepted PY - 2019/9/10/pubmed PY - 2019/9/10/medline PY - 2019/9/10/entrez KW - Androgen independence prostate cancer KW - CD44 KW - CYP19A1 KW - Endogenous estrogenic effects KW - MMP12 SP - 72 EP - 84 JF - Cancer letters JO - Cancer Lett. VL - 467 N2 - Castration-resistant prostate cancer (CRPC) following androgen deprivation therapy remains a major obstacle advanced prostate cancer management. Aromatase catalyzes estrogen from androgens, yet the role of aromatase-generated endogenous estrogen in CRPC is poorly understood. In this study, we assessed the expression and function of aromatase in CRPC. We found that aromatase expression was significantly increased in CRPC tissues and cell lines. In some prostate cancer cell lines, aromatase was predominantly expressed in CD44+ subsets. Bicalutamide treatment significantly increased aromatase expression, and CYP19A1 expression positively correlated with estrogen responses and epithelial-mesenchymal transition. Aromatase knockdown in PC3 cells reduced invasiveness and decreased metastasis-related gene expression. The aromatase inhibitor, letrozole, attenuated tumour metastasis in castrated PC3-xenograft mice. Mechanistically, aromatase-induced endogenous estrogen promoted estrogen receptor-α (ERα) binding to matrix metalloproteinase 12 (MMP12) promoter estrogen response element (ERE). MMP12 co-localized with CD44 on the cell membrane and MMP12 knockdown significantly reduced estradiol-induced PC3 invasion. Taken together, our findings indicated that increased endogenous estrogen, catalysed by elevated aromatase levels, enhanced MMP12 expression via ERα, participated in CRPC progression and promoted tumour metastasis. Thus, aromatase represents a potential novel therapeutic target for CRPC. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/31499120/Aromatase-induced_endogenous_estrogen_promotes_tumour_metastasis_through_estrogen_receptor-α/matrix_metalloproteinase_12_axis_activation_in_castration-resistant_prostate_cancer L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(19)30465-3 DB - PRIME DP - Unbound Medicine ER -