17β-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation

Tingting Yang; Zhen Qiu; Jiaming Shen; Yutian He; Longxiang Yin; Li Chen; Jiayu Yuan; Junjie Liu; Tao Wang; Zhenzhou Jiang; Changjiang Ying; Sitong Qian; Jinfang Song; Xiaoxing Yin; Qian Lu

doi:10.1016/j.jpha.2024.03.003

Volume 14 Issue 9

Sep. 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(9): 100962

Tingting Yang, Zhen Qiu, Jiaming Shen, Yutian He, Longxiang Yin, Li Chen, Jiayu Yuan, Junjie Liu, Tao Wang, Zhenzhou Jiang, Changjiang Ying, Sitong Qian, Jinfang Song, Xiaoxing Yin, Qian Lu. 17β-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation[J]. Journal of Pharmaceutical Analysis, 2024, 14(9): 100962. doi: 10.1016/j.jpha.2024.03.003

Citation:

Tingting Yang, Zhen Qiu, Jiaming Shen, Yutian He, Longxiang Yin, Li Chen, Jiayu Yuan, Junjie Liu, Tao Wang, Zhenzhou Jiang, Changjiang Ying, Sitong Qian, Jinfang Song, Xiaoxing Yin, Qian Lu. 17β-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation[J]. Journal of Pharmaceutical Analysis, 2024, 14(9): 100962. doi: 10.1016/j.jpha.2024.03.003

Citation:

Tingting Yang, Zhen Qiu, Jiaming Shen, Yutian He, Longxiang Yin, Li Chen, Jiayu Yuan, Junjie Liu, Tao Wang, Zhenzhou Jiang, Changjiang Ying, Sitong Qian, Jinfang Song, Xiaoxing Yin, Qian Lu. 17β-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation[J]. Journal of Pharmaceutical Analysis, 2024, 14(9): 100962. doi: 10.1016/j.jpha.2024.03.003

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17β-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation

doi: 10.1016/j.jpha.2024.03.003

a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China;
b Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China;
c Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China;
d New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China;
e Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China;
f Department of Pharmacy, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214000, China

Funds:

The work was supported by the National Natural Science Foundation of China (Grant Nos.: 82073906 and 82273987), Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, and Postgraduate Research Practice Innovation Program of Jiangsu Province (Grant Nos.: KYCX22-2966 and KYCX23-2967).

Received Date: Dec. 11, 2023
Accepted Date: Mar. 06, 2024
Rev Recd Date: Feb. 18, 2024
Publish Date: Mar. 12, 2024

Abstract

Abstract

Benign prostatic hyperplasia (BPH) is one of the major chronic complications of type 2 diabetes mellitus (T2DM), and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH. The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients, including simple BPH patients, newly diagnosed T2DM patients, T2DM complicated with BPH patients and matched healthy individuals. The G protein-coupled estrogen receptor (GPER) inhibitor G15, GPER knockdown lentivirus, the YAP1 inhibitor verteporfin, YAP1 knockdown/overexpression lentivirus, targeted metabolomics analysis, and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH. The homeostasis of sex steroid hormone is disrupted in the serum of patients, accompanying with the proliferated prostatic epithelial cells (PECs). The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals. Elevated 17β-estradiol (E2) is the key contributor to the disrupted sex steroid hormone homeostasis, and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH. Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose (HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer. Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells. The anti-proliferative effects of verteporfin, an inhibitor of YAP1, are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells. Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.
- Sex steroid hormone homeostasis,
- Proliferation,
- 17β-Estradiol,
- G protein-coupled estrogen receptor,
- T2DM complicated with BPH,
- Hippo-YAP1 signaling

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References(66)

References

[1]	A.A.A. Saad, F. Zhang, M. Refat, et al., Tamsulosin alters the pharmacokinetics of metformin via inhibition of renal multidrug and toxin extrusion protein 1 and organic cation transporter 2 in rats, J. Pharm. Biomed. Anal. 212 (2022), 114666.
[2]	J. Gandhi, S.J. Weissbart, A.N. Kim, et al., Clinical considerations for intravesical prostatic protrusion in the evaluation and management of bladder outlet obstruction secondary to benign prostatic hyperplasia, Curr. Urol. 12 (2018) 6-12.
[3]	B.R. Jin, H.J. An, Baicalin alleviates benign prostate hyperplasia through androgen-dependent apoptosis, Aging 12 (2020) 2142-2155.
[4]	J. Hammarsten, B. Hogstedt, Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia, Eur. Urol. 39 (2001) 151-158.
[5]	H. Nandeesha, B.C. Koner, L.N. Dorairajan, et al., Hyperinsulinemia and dyslipidemia in non-diabetic benign prostatic hyperplasia, Clin. Chim. Acta 370 (2006) 89-93.
[6]	B.R. Erdogan, G. Liu, E. Arioglu-Inan, et al., Established and emerging treatments for diabetes-associated lower urinary tract dysfunction, Naunyn Schmiedebergs Arch. Pharmacol. 395 (2022) 887-906.
[7]	W.J. Bang, J.Y. Lee, K.C. Koo, et al., Is type-2 diabetes mellitus associated with overactive bladder symptoms in men with lower urinary tract symptoms? Urology 84 (2014) 670-674.
[8]	A.E. Calogero, G. Burgio, R.A. Condorelli, et al., Epidemiology and risk factors of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction, Aging Male 22 (2019) 12-19.
[9]	H. Nandeesha, Benign prostatic hyperplasia: Dietary and metabolic risk factors, Int. Urol. Nephrol. 40 (2008) 649-656.
[10]	J.A. Santos-Marcos, M. Mora-Ortiz, M. Tena-Sempere, et al., Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases, Biol. Sex Differ. 14 (2023), 4.
[11]	A. Kautzky-Willer, J. Harreiter, G. Pacini, Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus, Endocr. Rev. 37 (2016) 278-316.
[12]	A. Gambineri, C. Pelusi, Sex hormones, obesity and type 2 diabetes: Is there a link? Endocr. Connect. 8 (2019) R1-R9.
[13]	R.E. van Genugten, K.M. Utzschneider, J. Tong, et al., Effects of sex and hormone replacement therapy use on the prevalence of isolated impaired fasting glucose and isolated impaired glucose tolerance in subjects with a family history of type 2 diabetes, Diabetes 55 (2006) 3529-3535.
[14]	G. Blohme, L. Nystrom, H.J. Arnqvist, et al., Male predominance of type 1 (insulin-dependent) diabetes mellitus in young adults: Results from a 5-year prospective nationwide study of the 15-34-year age group in Sweden, Diabetologia 35 (1992) 56-62.
[15]	J. Li, H. Lai, S. Chen, et al., Interaction of sex steroid hormones and obesity on insulin resistance and type 2 diabetes in men: The third national health and nutrition examination survey, J. Diabetes Complicat. 31 (2017) 318-327.
[16]	J. Hu, A. Zhang, S. Yang, et al., Combined effects of sex hormone-binding globulin and sex hormones on risk of incident type 2 diabetes, J. Diabetes 8 (2016) 508-515.
[17]	T. Muka, J. Nano, L. Jaspers, et al., Associations of steroid sex hormones and sex hormone-binding globulin with the risk of type 2 diabetes in women: A population-based cohort study and meta-analysis, Diabetes 66 (2017) 577-586.
[18]	Y. Piao, P. Wiesenfeld, R. Sprando, et al., TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment? J. Steroid Biochem. Mol. Biol. 138 (2013) 206-213.
[19]	Y. Kim, D. Lee, H. Jo, et al., GV1001 interacts with androgen receptor to inhibit prostate cell proliferation in benign prostatic hyperplasia by regulating expression of molecules related to epithelial-mesenchymal transition, Aging. (Albany NY) 13 (2021) 3202-3217.
[20]	C.K.M. Ho, F.K. Habib, Estrogen and androgen signaling in the pathogenesis of BPH, Nat. Rev. Urol. 8 (2011) 29-41.
[21]	G. Rastrelli, L. Vignozzi, G. Corona, et al., Testosterone and benign prostatic hyperplasia, Sex. Med. Rev. 7 (2019) 259-271.
[22]	E. Csikos, A. Horvath, K. Acs, et al., Treatment of benign prostatic hyperplasia by natural drugs, Molecules 26 (2021), 7141.
[23]	L. Pan, S. Su, Y. Li, et al., The effect of acupuncture on oestrogen receptors in rats with benign prostatic hyperplasia, J. Steroid Biochem. Mol. Biol. 234 (2023), 106402.
[24]	T. Yang, Y. Huang, Y. Zhou, et al., Simultaneous quantification of oestrogens and androgens in the serum of patients with benign prostatic hyperplasia by liquid chromatography-Tandem mass spectrometry, Andrologia 52 (2020), e13611.
[25]	T. Yang, Y. Zhou, H. Wang, et al., Insulin exacerbated high glucose-induced epithelial-mesenchymal transition in prostatic epithelial cells BPH-1 and prostate cancer cells PC-3 via MEK/ERK signaling pathway, Exp. Cell Res. 394 (2020), 112145.
[26]	S.W. Fanning, L. Hodges-Gallagher, D.C. Myles, et al., Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity, Nat. Commun. 9 (2018), 2368.
[27]	T. Yang, J. Yuan, Y. Peng, et al., Metformin: A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation, J. Pharm. Anal. 14 (2024) 52-68.
[28]	Y.Y. Liu, L. Li, B. Ji, et al., Jujuboside A ameliorates tubulointerstitial fibrosis in diabetic mice through down-regulating the YY1/TGF-β1 signaling pathway, Chin. J. Nat. Med. 20 (2022) 656-668.
[29]	X. Qian, L. He, M. Hao, et al., YAP mediates the interaction between the Hippo and PI3K/Akt pathways in mesangial cell proliferation in diabetic nephropathy, Acta Diabetol. 58 (2021) 47-62.
[30]	Y. Liu, Z. Tang, Y. Zhang, et al., Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes, Biochem. Pharmacol. 175 (2020), 113849.
[31]	R. Wang, Z. Qiu, G. Wang, et al., Quercetin attenuates diabetic neuropathic pain by inhibiting mTOR/p70S6K pathway-mediated changes of synaptic morphology and synaptic protein levels in spinal dorsal horn of db/db mice, Eur. J. Pharmacol. 882 (2020), 173266.
[32]	T. Yang, C. Heng, Y. Zhou, et al., Targeting mammalian serine/threonine-protein kinase 4 through Yes-associated protein/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis, Metabolism 108 (2020), 154258.
[33]	E.R. Prossnitz, M. Barton, The G-protein-coupled estrogen receptor GPER in health and disease, Nat. Rev. Endocrinol. 7 (2011) 715-726.
[34]	X. Zhou, S. Wang, Z. Wang, et al., Estrogen regulates Hippo signaling via GPER in breast cancer, J. Clin. Invest. 125 (2015) 2123-2135.
[35]	Q. Deng, G. Jiang, Y. Wu, et al., GPER/Hippo-YAP signal is involved in Bisphenol S induced migration of triple negative breast cancer (TNBC) cells, J. Hazard. Mater. 355 (2018) 1-9.
[36]	E. Donohue, A. Thomas, N. Maurer, et al., The autophagy inhibitor verteporfin moderately enhances the antitumor activity of gemcitabine in a pancreatic ductal adenocarcinoma model, J. Cancer 4 (2013) 585-596.
[37]	H.Z. Sun, T.W. Yang, W.J. Zang, et al., Dehydroepiandrosterone-induced proliferation of prostatic epithelial cell is mediated by NFKB via PI3K/AKT signaling pathway, J. Endocrinol. 204 (2010) 311-318.
[38]	K. Griffiths, C.L. Eaton, M.E. Harper, et al., Steroid hormones and the pathogenesis of benign prostatic hyperplasia, Eur. Urol. 20 Suppl 1 (1991) 68-77.
[39]	J.B. Arterburn, E.R. Prossnitz, G protein-coupled estrogen receptor GPER: Molecular pharmacology and therapeutic applications, Annu. Rev. Pharmacol. Toxicol. 63 (2023) 295-320.
[40]	L. Aryan, D. Younessi, M. Zargari, et al., The role of estrogen receptors in cardiovascular disease, Int. J. Mol. Sci. 21 (2020), 4314.
[41]	S.K. Kim, J.H. Chung, H.C. Park, et al., Association between polymorphisms of estrogen receptor 2 and benign prostatic hyperplasia, Exp. Ther. Med. 10 (2015) 1990-1994.
[42]	R. Chen, Y. Yu, X. Dong, Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer, J. Steroid Biochem. Mol. Biol. 166 (2017) 91-96.
[43]	Y. Yang, J. Sheng, S. Hu, et al., Estrogen and G protein-coupled estrogen receptor accelerate the progression of benign prostatic hyperplasia by inducing prostatic fibrosis, Cell Death Dis. 13 (2022) 533.
[44]	D.L. Yang, J.W. Xu, J.G. Zhu, et al., Role of GPR30 in estrogen-induced prostate epithelial apoptosis and benign prostatic hyperplasia, Biochem. Biophys. Res. Commun. 487 (2017) 517-524.
[45]	W. Dong, J. Zheng, Y. Huang, et al., Sodium butyrate treatment and fecal microbiota transplantation provide relief from ulcerative colitis-induced prostate enlargement, Front. Cell Infect. Microbiol. 12 (2022), 1037279.
[46]	Y. Wang, H. Yu, J. He, Involvement of the hippo pathway in the development of diabetes, Discov. Med. 31 (2021) 37-44.
[47]	X. Li, S. Zhuo, Y.S. Cho, et al., YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth, EMBO J. 42 (2023), e112184.
[48]	L. Du, C. Li, X. Qian, et al., Quercetin inhibited mesangial cell proliferation of early diabetic nephropathy through the Hippo pathway, Pharmacol. Res. 146 (2019), 104320.
[49]	J.C. Cheng, L. Fang, Y. Li, et al., G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression, Commun. Biol. 4 (2021) 1285.
[50]	F. Yu, B. Zhao, N. Panupinthu, et al., Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling, Cell 150 (2012) 780-791.
[51]	Y. Zhao, H. Liu, M. Fan, et al., G protein-coupled receptor 30 mediates cell proliferation of goat mammary epithelial cells via MEK/ERK&PI3K/AKT signaling pathway, Cell Cycle 21 (2022) 2027-2037.
[52]	X. Sheng, W. Li, D. Wang, et al., YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells, Mol. Med. Rep. 12 (2015) 4867-4876.
[53]	E. Desideri, S. Castelli, C. Dorard, et al., Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells, Autophagy 19 (2023) 152-162.
[54]	T. Han, T. Chen, L. Chen, et al., HLF promotes ovarian cancer progression and chemoresistance via regulating Hippo signaling pathway, Cell Death Dis. 14 (2023), 606.
[55]	H. Chen, W. Yang, Y. Li, et al., PLAGL2 promotes bladder cancer progression via RACGAP1/RhoA GTPase/YAP1 signaling, Cell Death Dis. 14 (2023), 433.
[56]	R.D. Read, Repurposing the drug verteporfin as anti-neoplastic therapy for glioblastoma, Neuro Oncol. 24 (2022) 708-710.
[57]	X. Li, L. Fan, M. Zhu, et al., Combined intervention of 17β-estradiol and treadmill training ameliorates energy metabolism in skeletal muscle of female ovariectomized mice, Climacteric 23 (2020) 192-200.
[58]	A. Inada, N.L. Fujii, O. Inada, et al., Effects of 17β-estradiol and androgen on glucose metabolism in skeletal muscle, Endocrinology 157 (2016) 4691-4705.
[59]	Z. Bao, Z.Q. Liu, P.Y. He, et al., 17β-estradiol regulates adenosine triphosphate-binding cassette transporters A1 expression via estrogen receptor A to increase macrophage cholesterol efflux, J. Physiol. Pharmacol. 74 (2023), https://doi.org/ 10.26402/jpp.2023.5.05.
[60]	M. Wang, F. Gorelick, A. Bhargava, Sex differences in the exocrine pancreas and associated diseases, Cell. Mol. Gastroenterol. Hepatol. 12 (2021) 427-441.
[61]	S. Nikanfar, H. Oghbaei, Y. Rastgar Rezaei, et al., Role of adipokines in the ovarian function: Oogenesis and steroidogenesis, J. Steroid Biochem. Mol. Biol. 209 (2021), 105852.
[62]	M. Pektas, A.H. Kurt, I. Un, et al., Effects of 17β-estradiol and progesterone on the production of adipokines in differentiating 3T3-L1 adipocytes: Role of rho-kinase, Cytokine 72 (2015) 130-134.
[63]	K. Rabe, M. Lehrke, K.G. Parhofer, et al., Adipokines and insulin resistance, Mol. Med. 14 (2008) 741-751.
[64]	B. Carrillo, P. Collado, F. Diaz, et al., Blocking of estradiol receptors ERα, ERβ and GPER during development, differentially alters energy metabolism in male and female rats, Neuroscience 426 (2020) 59-68.
[65]	F. Mahboobifard, M.H. Pourgholami, M. Jorjani, et al., Estrogen as a key regulator of energy homeostasis and metabolic health, Biomed. Pharmacother. 156 (2022), 113808.
[66]	M. Shen, H. Shi, Sex hormones and their receptors regulate liver energy homeostasis, Int. J. Endocrinol. 2015 (2015), 294278.