Glucose-regulated protein 78 modulates cell growth, epithelial\u2013mesenchymal transition, and oxidative stress in the hyperplastic prostate

Xun Fu,Xinhua Zhang,Zhen Wang,Weixiang He,Daoquan Liu,Shu Yang,Yongying Zhou,Ping Chen,Yuhang Guo,Xinghuan Wang,Michael E Disanto,Jianmin Liu

doi:10.1038/s41419-022-04522-4

Abstract

Benign prostatic hyperplasia (BPH) is a chronic condition which mainly affects elderly males. Existing scientific evidences have not completely revealed the pathogenesis of BPH. Glucose-regulated protein 78 (GRP78) is a member of the heat shock protein 70 superfamily, which serves as an important regulator in many diseases. This study aims at elucidating the role of GRP78 in the BPH process. Human prostate tissues, cultured human prostate cell lines (BPH-1 and WPMY-1) and clinical data from BPH patients were utilized. The expression and localization of GRP78 were determined with quantitative real time PCR (qRT-PCR), Western blotting and immunofluorescence staining. GRP78 knockdown and overexpression cell models were created with GRP78 siRNA and GRP78 plasmid transfection. With these models, cell viability, apoptosis rate, as well as marker levels for epithelial-mesenchymal transition (EMT) and oxidative stress (OS) were detected by CCK8 assay, flow cytometry analysis and Western blotting respectively. AKT/mTOR and MAPK/ERK pathways were also evaluated. Results showed GRP78 was localized in the epithelium and stroma of the prostate, with higher expression in BPH tissues. There was no significant difference in GRP78 expression between BPH-1 and WPMY-1 cell lines. In addition, GRP78 knockdown (KD) slowed cell growth and induced apoptosis, without effects on the cell cycle stage of both cell lines. Lack of GRP78 affected expression levels of markers for EMT and OS. Consistently, overexpression of GRP78 completely reversed all effects of knocking down GRP78. We further found that GRP78 modulated cell growth and OS via AKT/mTOR signaling, rather than the MAPK/ERK pathway. Overall, our novel data demonstrates that GRP78 plays a significant role in the development of BPH and suggests that GRP78 might be rediscovered as a new target for treatment of BPH.

Highlights

Benign prostatic hyperplasia (BPH) is a common chronic disease in elderly men [1]
SC79 completely reversed attenuated addition, Glucose-regulated protein 78 (GRP78) was localized in both epithelial and stromal cell viability caused by GRP78 silencing (Fig. 5A). siGRP78-induced compartments of prostate tissues (Fig. 1G), and apoptosis was rescued by SC79 (Fig. 5B, C)
This it was stained at the membrane or the cytoplasm, rather than the activator recovered the expression of apoptosis-related proteins nucleus, of BPH-1 and WPMY-1 cell lines (Fig. 1H)

Summary

Introduction

Benign prostatic hyperplasia (BPH) is a common chronic disease in elderly men [1]. Accumulating evidence shows that its incidence increases with age [2]. More than 80% of men over 70 years old are troubled by this disease worldwide [3]. A number of pathophysiological hypotheses of BPH have been proposed, including the imbalance of androgen-estrogen ratio; the dysregulation of cell proliferation and apoptosis; the interaction between stromal and epithelial cells; inflammation; as well as growth factors [4]. The prostate cells are often subjected to severe OS due to obesity [5], smoking and aging [6, 7]. It is already well accepted that this process contributes to accumulation of stromal cells in the prostate [9]. The exact molecular mechanism of BPH has not been fully elucidated

Objectives

Methods

Results

Conclusion