FKBP51 decreases cell proliferation and increases progestin sensitivity of human endometrial adenocarcinomas by inhibiting Akt.

Jing Dong,Linying Sun,Xiaowen Liu,Zijiang Chen,Shengnan Hu,Yulian Jiao,Bingru Lu,Muyun Wei,Bin Cui,Wenli Mu,Yueran Zhao

doi:10.18632/oncotarget.18903

Jing Dong, Linying Sun + Show 9 more

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https://doi.org/10.18632/oncotarget.18903

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Journal: Oncotarget	Publication Date: Jun 30, 2017
Citations: 8	License type: cc-by

Affiliation: Shandong Provincial Hospital, Shandong University

Abstract

In this study, we investigated the role of FK506 binding protein 51 (FKBP51) in human endometrial adenocarcinoma progression. Immunohistochemical analysis showed decreased FKBP51 expression in endometrial adenocarcinoma tissues. Moreover, higher FKBP51 expression was observed in the normal secretory phase than in proliferative-phase endometrial tissues. FKBP51-shRNA transfected KLE cells showed high Ser473-phospho Akt with decreased p21 and p27 levels, which promoted S-G2/M phase cell cycle progression and proliferation. Conversely, FKBP51 overexpressing Ishikawa cells showed low Ser473-phospho Akt, which led to increased p21 and p27 levels and, in turn, G0/G1 cell cycle arrest and decreased cell proliferation. FKBP51 overexpression in progesterone receptor-positive Ishikawa cells sensitized them to medroxyprogesterone acetate (MPA; progestin) treatment by repressing Akt signaling. Conversely, FKBP51-shRNA knockdown in RL95-2 cells attenuated progestin sensitivity. These findings indicate FKBP51 inhibits cell proliferation and promotes progestin sensitivity in endometrial adenocarcinoma by decreasing Akt signaling.

Highlights

FK506 binding protein 51 (FKBP51) is a 51-kDa protein that belongs to a family of FK506-binding proteins and contains FK506 binding and tetratricopeptide repeat (TPR) domains [1, 2]
We investigated the role of FK506 binding protein 51 (FKBP51) in human endometrial adenocarcinoma progression
FKBP51 expression was lower in proliferative phase than in the secretory phase (Figure 1A, 1C)

Summary

Introduction

FK506 binding protein 51 (FKBP51) is a 51-kDa protein that belongs to a family of FK506-binding proteins and contains FK506 binding and tetratricopeptide repeat (TPR) domains [1, 2]. Human FKBP51 has two consecutive FK506 binding domains (FK1 and FK2), only FK1 interacts with immunosuppressants and possesses the peptidylprolyl isomerase (PPIase) activity, thereby acting as an NF-κB activator [3]. Both FK domains are involved in Akt binding, whereas the three-unit repeat of the TPR domain in the C-terminus forms super-chaperone complexes with heat shock proteins and steroid receptors and modulates steroid receptor activity [4,5,6,7]. FKBP51 is expressed in many normal human tissues and overexpressed or downregulated in various human cancers [9]. FKBP51 is downregulated in pancreatic cancer and impairs cellular responses to chemotherapy through the PI3K/AKT signaling pathway [12,13,14,15,16]

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