Pao Pereira extract suppresses benign prostatic hyperplasia by inhibiting inflammation-associated NFκB signaling

Yunsheng Dong1, Jiakuan Liu2, Zhaoli Xue2, Jingya Sun3, Zhengnan Huang4, Yifeng Jing4, Bangmin Han4, Bing Shen4, Jun Yan5, Ruimin Huang6
1Shanghai University, Shanghai, China
2Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China
3Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
4Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, 200080, China
5Department of Laboratory Animal Science, Fudan University, 130 Dong’an Road, Shanghai, 200032, China
6University of Chinese Academy of Sciences, Beijing, 100049, China

Tóm tắt

Abstract Background

Our previous study revealed the extract from the bark of an Amazonian tree Pao Pereira can suppress benign prostatic hyperplasia (BPH) in a rat model. Herein, we examined its inhibitory effects on human BPH cells and dissect its molecular mechanism.

Methods

We applied Pao extract to human BPH epithelial BPH-1 and prostate myofibroblast WPMY-1 cells. Cell viability, apoptosis and immunoblotting were performed, followed by gene expression profiling and gene set enrichment analysis (GSEA) to detect the differentially expressed genes and signaling pathway induced by Pao extract. Human ex vivo BPH explant organ culture was also used to examine the effects of Pao extract on human BPH tissues.

Results

Pao extract treatment inhibited viability and induced apoptosis in human BPH-1 and WPMY-1 cells. Gene expression profiling and the following validation indicated that the expression levels of pro-apoptotic genes (eg. PCDC4, CHOP and FBXO32) were induced by Pao extract in both two cell lines. GSEA further revealed that Pao extract treatment was negatively associated with the activation of NFκB signaling. Pao extract suppressed the transcriptional activity of NFκB and down-regulated its target genes involved in inflammation (CXCL5, CXCL6 and CXCL12) and extracellular matrix (ECM) remodeling (HAS2, TNC and MMP13) in both cultured cells and human ex vivo BPH explants.

Conclusion

In both BPH epithelial and stromal cells, Pao extract induces apoptosis by upregulating the pro-apoptotic genes and inhibiting the inflammation-associated NFκB signaling via reducing phosphorylation of NFκB subunit RelA. Our data suggest that Pao extract may be a promising phytotherapeutic agent for BPH.

Từ khóa


Tài liệu tham khảo

Hellwege JN, Stallings S, Torstenson ES, Carroll R, Borthwick KM, Brilliant MH, et al. Heritability and genome-wide association study of benign prostatic hyperplasia (BPH) in the eMERGE network. Sci Rep. 2019;9(1):6077.

Bushman W. Etiology, epidemiology, and natural history of benign prostatic hyperplasia. Urol Clin North Am. 2009;36(4):403–15 v.

Lepor H. Pathophysiology, epidemiology, and natural history of benign prostatic hyperplasia. Rev Urol. 2004;6(Suppl 9):S3.

Chughtai B, Forde JC, Thomas DDM, Laor L, Hossack T, Woo HH, et al. Benign prostatic hyperplasia. Nat Rev Dis Primers. 2016;2:16031.

Kapoor A. Benign prostatic hyperplasia (BPH) management in the primary care setting. Can J Urol. 2012;19(Suppl 1):10–7.

Theyer G, Kramer G, Assmann I, Sherwood E, Preinfalk W, Marberger M, et al. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab Investig. 1992;66(1):96–107.

Robert G, Descazeaud A, Nicolaïew N, Terry S, Sirab N, Vacherot F, et al. Inflammation in benign prostatic hyperplasia: a 282 patients’ immunohistochemical analysis. Prostate. 2009;69(16):1774–80.

Bemis DL, Capodice JL, Desai M, Katz AE, Buttyan R. β-Carboline alkaloid–enriched extract from the Amazonian rain forest tree pao Pereira suppresses prostate cancer cells. J Soc Integr Oncol. 2009;7(2):59.

Yu J, Drisko J, Chen Q. Inhibition of pancreatic cancer and potentiation of gemcitabine effects by the extract of Pao Pereira. Oncol Rep. 2013;30(1):149–56.

Dong R, Chen P, Chen Q. Extract of the medicinal plant Pao Pereira inhibits pancreatic cancer stem-like cell in vitro and in vivo. Integr Cancer Ther. 2018;17(4):1204–15.

Beljanski M, Crochet S. The selective anticancer agent pb-100 inhibits interleukin-6 induced enhancement of glioblastoma cell-proliferation in-vitro. Int J Oncol. 1994;5(4):873–9.

Beljanski M, Crochet S. The anticancer agent pb-100 concentrates in the nucleus and nucleoli of human glioblastoma cells but does not enter normal astrocytes. Int J Oncol. 1995;7(1):81–5.

Yu J, Chen Q. The plant extract of Pao Pereira potentiates carboplatin effects against ovarian cancer. Pharm Biol. 2014;52(1):36–43.

Chang C, Zhao W, Xie B, Deng Y, Han T, Cui Y, et al. Pao Pereira extract suppresses castration-resistant prostate cancer cell growth, survival, and invasion through inhibition of NfκB signaling. Integr Cancer Ther. 2014;13(3):249–58.

Liu J, Fang T, Li M, Song Y, Li J, Xue Z, et al. Pao Pereira extract attenuates testosterone-induced benign prostatic hyperplasia in rats by inhibiting 5α-reductase. Sci Rep. 2019;9(1):19703.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.

Centenera MM, Gillis JL, Hanson AR, Jindal S, Taylor RA, Risbridger GP, et al. Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. Clin Cancer Res. 2012;18(13):3562–70.

Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134–49.

Austin DC, Strand DW, Love HL, Franco OE, Jang A, Grabowska MM, et al. NF-κB and androgen receptor variant expression correlate with human BPH progression. Prostate. 2016;76(5):491–511.

Penna G, Fibbi B, Amuchastegui S, Corsiero E, Laverny G, Silvestrini E, et al. The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/rho kinase and NF-kappaB pathways. Prostate. 2009;69(5):480–93.

Hwang S-K, Baker AR, Young MR, Colburn NH. Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65. Carcinogenesis. 2014;35(7):1469–80.

Guan Z, Li C, Fan J, He D, Li L. Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling. Sci Rep. 2016;6:37085.

Lisi S, Sisto M, Lofrumento DD, D'amore M. Sjögren's syndrome autoantibodies provoke changes in gene expression profiles of inflammatory cytokines triggering a pathway involving TACE/NF-κB. Lab Investig. 2012;92(4):615.

Madge LA, May MJ. Classical NF-kappaB activation negatively regulates noncanonical NF-kappaB-dependent CXCL12 expression. J Biol Chem. 2010;285(49):38069–77.

Begley LA, Kasina S, MacDonald J, Macoska JA. The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy. Cytokine. 2008;43(2):194–9.

Maroni P, Bendinelli P, Matteucci E, Desiderio MA. HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB. Carcinogenesis. 2007;28(2):267–79.

Smith JB, Wadleigh DJ, Xia YR, Mar RA, Herschman HR, Lusis AJ. Cloning and genomic localization of the murine LPS-induced CXC chemokine (LIX) gene, Scyb5. Immunogenetics. 2002;54(8):599–603.

Damodarasamy M, Vernon RB, Chan CK, Plymate SR, Wight TN, Reed MJ. Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation. In Vitro Cell Dev Biol Anim. 2015;51(1):50–8.

Yoo KC, Suh Y, An Y, Lee HJ, Jeong YJ, Uddin N, et al. Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation. Oncogene. 2018;37(24):3317–28.

Nakoshi Y, Hasegawa M, Sudo A, Yoshida T, Uchida A. Regulation of tenascin-C expression by tumor necrosis factor-alpha in cultured human osteoarthritis chondrocytes. J Rheumatol. 2008;35(1):147–52.

Ishii K, Imanaka-Yoshida K, Yoshida T, Sugimura Y. Role of stromal tenascin-C in mouse prostatic development and epithelial cell differentiation. Dev Biol. 2008;324(2):310–9.