Role of GDF15 in methylseleninic acid-mediated inhibition of cell proliferation and induction of apoptosis in prostate cancer cells

PLoS One. 2019 Sep 20;14(9):e0222812. doi: 10.1371/journal.pone.0222812. eCollection 2019.

Abstract

The growth inhibitory efficacy of methylseleninic acid (MSA) in prostate cancer cells has been documented extensively. However, our understanding of the immediate targets that are key to the growth inhibitory effects of MSA remains limited. Here, using multiple preclinical prostate cancer models, we demonstrated in vitro and in vivo that GDF15 is a most highly induced, immediate target of MSA. We further showed that knockdown of GDF15 mitigates MSA inhibition of cell proliferation and induction of apoptosis. Analysis of gene expression data from over 1000 primary and 200 metastatic prostate cancer samples revealed that GDF15 expression is decreased in metastatic prostate cancers compared to primary tumors and that lower GDF15 levels in primary tumors are associated with higher Gleason scores and shorter survival of the patients. Additionally, pathways that are negatively correlated with GDF15 levels in clinical samples are also negatively correlated with MSA treatment in cultured cells. Since most, if not all, of these pathways have been implicated in prostate cancer progression, suppressing their activities by inducing GDF15 is consistent with the anticancer effects of MSA in prostate cancer. Overall, this study provides support for GDF15 as an immediate target of MSA in prostate cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / metabolism*
  • Humans
  • Male
  • Organoselenium Compounds / pharmacology*
  • PC-3 Cells
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Proteomics / methods

Substances

  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Organoselenium Compounds
  • methylselenic acid

Grants and funding

Y.Z. was funded by Jilin Scientific and Technological Development Program and the Grant No. 20180414034GH. The website is http://kjt.jl.gov.cn/. J.G. was funded by the National Natural Science Foundation of China Project 81430087. The website is http://www.nsfc.gov.cn/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.