Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Antineoplastic Agents/*pharmacology ; Breast Neoplasms/*drug therapy ; Dimethyl Sulfoxide/*pharmacology ; Down-Regulation/*drug effects ; STAT3 Transcription Factor/*metabolism ; STAT5 Transcription Factor/*metabolism ; Sulfones/*pharmacology; Animals ; Apoptosis/drug effects ; COS Cells ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Chlorocebus aethiops ; Female ; Gene Expression ; Humans ; Inhibitory Concentration 50 ; Mice ; Promoter Regions, Genetic ; Protein Binding ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; STAT3 Transcription Factor/genetics ; STAT5 Transcription Factor/genetics ; Tumor Burden/drug effects ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor A/metabolism ; Xenograft Model Antitumor Assays

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers.

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0 (Antineoplastic Agents)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
0 (STAT5 Transcription Factor)
0 (STAT5B protein, human)
0 (Sulfones)
0 (VEGFA protein, human)
0 (Vascular Endothelial Growth Factor A)
9H4PO4Z4FT (dimethyl sulfone)
EC 2.7.10.1 (Receptor, IGF Type 1)
YOW8V9698H (Dimethyl Sulfoxide)

Date Created: 20120410 Date Completed: 20120727 Latest Revision: 20211021

20250114

PMC3317666

10.1371/journal.pone.0033361

22485142