Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells

Nana Pei; Feilong Jie; Jie Luo; Renqiang Wan; Yanling Zhang; Xinglu Chen; Zhibing Liang; Hongyan Du; Andrew Li; Baihong Chen; Yi Zhang; Colin Sumners; Jinlong Li; Weiwang Gu; Hongwei Li

doi:10.1371/journal.pone.0092253

Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells

PLoS One. 2014 Mar 21;9(3):e92253. doi: 10.1371/journal.pone.0092253. eCollection 2014.

Authors

Nana Pei¹, Feilong Jie¹, Jie Luo¹, Renqiang Wan², Yanling Zhang¹, Xinglu Chen¹, Zhibing Liang¹, Hongyan Du¹, Andrew Li³, Baihong Chen¹, Yi Zhang⁴, Colin Sumners⁵, Jinlong Li¹, Weiwang Gu⁶, Hongwei Li¹

Affiliations

¹ School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
² Department of Otolaryngology-Head and Neck Surgery, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong, China.
³ Department of Neuroscience, University of Florida, Gainesville, Florida, United States of America.
⁴ Department of Pharmacology, University of Florida, Gainesville, Florida, United States of America.
⁵ Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, United States of America.
⁶ Institute of Comparative Medicine and Center of Laboratory Animals, Southern Medical University, Guangzhou, Guangdong, China.

Abstract

Increased expression of angiotensin II type 2 receptor (AT2R) induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2), 2 cytokine genes (IL6 and IL8) and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7) in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.

Publication types

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

MeSH terms

Apoptosis / drug effects
Apoptosis / genetics*
Cell Line, Tumor
Down-Regulation
Gene Expression Profiling
Humans
Male
MicroRNAs / biosynthesis
Microarray Analysis
Prostatic Neoplasms / genetics
Prostatic Neoplasms / pathology*
Receptor, Angiotensin, Type 2 / metabolism*
Transduction, Genetic
Up-Regulation

Substances

MicroRNAs
Receptor, Angiotensin, Type 2

Grants and funding

This work was supported by National Natural Science Foundation of China Grant 81072113 (H.L.), National 863 High Technique Development Projects of China Grant 2012AA02A403 (H.L.), State Key Laboratory of Pathogen and Biosecurity Program SKLPBS1103 (H.L.), as well as by awards 2011A091000022, 2010B060500001, 2011B060300028 and 2011B060300014 to W.G. from the Chinese government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.