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

• Published in: PloS one Vol. 14; no. 9; p. e0222812
• Main Authors: Zhang, Wenbo, Hu, Cheng, Wang, Xiaojie, Bai, Shanshan, Cao, Subing, Kobelski, Margaret, Lambert, James R, Gu, Jingkai, Zhan, Yang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.09.2019; Public Library of Science (PLoS)
• Subjects: Abiraterone; Acids; Acquired immune deficiency syndrome; AIDS; Analysis; Androgens; Anticancer properties; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biochemistry; Biology and Life Sciences; Biomarkers; Cabazitaxel; Cancer cells; Cancer metastasis; Cancer research; Cancer therapies; Care and treatment; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cellular biology; Cytokines; Development and progression; Drug dosages; Engineering; Enzalutamide; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Humans; Laboratories; Life sciences; Male; Medical prognosis; Medicine; Medicine and Health Sciences; Metabolism; Metabolites; Metastases; Metastasis; Organoselenium Compounds - pharmacology; PC-3 Cells; Physical Sciences; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteomics - methods; Research and Analysis Methods; Selenium; Tumors; Vitamin E; Louisiana; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0222812

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.