STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer

Yingxi Xu; Shu Zhang; Haiying Niu; Yujie Ye; Fen Hu; Si Chen; Xuefei Li; Xiaohe Luo; Shan Jiang; Yanhua Liu; Yanan Chen; Junying Li; Rong Xiang; Na Li

doi:10.1038/srep11754

STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer

Sci Rep. 2015 Aug 10:5:11754. doi: 10.1038/srep11754.

Authors

Yingxi Xu¹, Shu Zhang², Haiying Niu³, Yujie Ye², Fen Hu⁴, Si Chen², Xuefei Li⁵, Xiaohe Luo², Shan Jiang², Yanhua Liu², Yanan Chen², Junying Li³, Rong Xiang⁶, Na Li⁶

Affiliations

¹ 1] School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] State Key Lab of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China.
² School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
³ Department of Obstetrics and Gynecology, First Central Hospital Clinic Institute, Tianjin Medical University, 24 Fukang Road, Tianjin 300192 China.
⁴ School of Physics, Nankai University, 94 Weijin Road, Tianjin 300071, China.
⁵ Beijing Health Vocational College, 94 Nanhengxijie Street, Beijing, 100053 China.
⁶ 1] School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China [2] Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin 300071, China [3] Collaborative Innovation Center for Biotherapy, Nankai University, 94 Weijin Road, Tianjin 300071, China.

Abstract

The importance of store-operated Ca(2+) entry (SOCE) and the role of its key molecular regulators, STIM1 and ORAI1, in the development of cancer are emerging. Here, we report an unexpected dual function of SOCE in prostate cancer progression by revealing a decrease in the expression of STIM1 in human hyperplasia and tumor tissues of high histological grade and by demonstrating that STIM1 and ORAI1 inhibit cell growth by arresting the G0/G1 phase and enhancing cell senescence in human prostate cancer cells. In addition, STIM1 and ORAI1 inhibited NF-κB signaling and remodeled the tumor microenvironment by reducing the formation of M2 phenotype macrophages, possibly creating an unfavorable tumor microenvironment and inhibiting cancer development. However, STIM1 also promoted cell migration and the epithelial-to-mesenchymal transition by activating TGF-β, Snail and Wnt/β-Catenin pathways. Thus, our study revealed novel regulatory effects and the mechanisms by which STIM1 affects cell senescence, tumor migration and the tumor microenvironment, revealing that STIM1 has multiple functions in prostate cancer cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium Channels / genetics
Calcium Channels / metabolism*
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cellular Senescence*
Down-Regulation
Epithelial-Mesenchymal Transition*
G1 Phase Cell Cycle Checkpoints
Humans
Macrophages / cytology
Macrophages / immunology
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred NOD
Mice, SCID
NF-kappa B / metabolism
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
ORAI1 Protein
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Signal Transduction
Snail Family Transcription Factors
Stromal Interaction Molecule 1
Transcription Factors / metabolism
Transforming Growth Factor beta / metabolism
Transplantation, Heterologous
Tumor Microenvironment
Wnt Proteins / metabolism
beta Catenin / metabolism

Substances

Calcium Channels
Membrane Proteins
NF-kappa B
Neoplasm Proteins
ORAI1 Protein
ORAI1 protein, human
STIM1 protein, human
Snail Family Transcription Factors
Stromal Interaction Molecule 1
Transcription Factors
Transforming Growth Factor beta
Wnt Proteins
beta Catenin