Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFβ/miR-21 signaling.

Abstract

Compelling efficacy on intervention of tumorigenesis by nonsteroidal anti-inflammatory drugs (NSAIDs) has been documented intensively. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID sulindac sulfide (SS), referred as sulindac sulfide amide (SSA), was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of various cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results show that SSA treatment at non-cytotoxic concentrations can specifically reduce breast tumor cell motility without influencing tumor cell growth, and the mechanism of action involves the suppression of TGFβ signaling by directly blocking Smad2/3 phosphorylation. Moreover, miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, was also found to be involved in inhibitory activity of SSA in breast tumor cell motility through the modulation of TGFβ pathway. In conclusion, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis by a mechanism involving the TGFβ/miR-21 signaling axis.

• Authors: Bin Yi, Hong Chang, Ruixia Ma, Xiangling Feng, Wei Li, Gary A Piazza, Yaguang Xi
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 7 Pg. 7979-92 (Feb 16 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26769851 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN21 microRNA, human
• MicroRNAs
• Transforming Growth Factor beta
• sulindac sulfide amide
• Sulindac

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chromatin Immunoprecipitation
• Female
• Fluorescent Antibody Technique
• Humans
• Immunoenzyme Techniques
• MicroRNAs (antagonists & inhibitors, genetics)
• Sulindac (analogs & derivatives, pharmacology)
• Transforming Growth Factor beta (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured
• Wound Healing