Research Papers:

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

Bin Yi, Hong Chang, Ruixia Ma, Xiangling Feng, Wei Li, Gary A. Piazza and Yaguang Xi _

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Oncotarget. 2016; 7:7979-7992. https://doi.org/10.18632/oncotarget.6888

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Bin Yi1,*, Hong Chang1,*, Ruixia Ma1, Xiangling Feng1,2, Wei Li3, Gary A. Piazza1, Yaguang Xi1

1Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

2School of Public Health, Central South University, Changsha, Hunan, China

3Department of Pharmaceutical Science, University of Tennessee Health Science Center, Memphis, TN, USA

*These authors have contributed equally to this work

Correspondence to:

Yaguang Xi, e-mail: xi@health.southalabama.edu

Keywords: sulindac, breast cancer, metastasis, microRNA, TGFβ

Received: September 15, 2015    Accepted: January 06, 2016    Published: January 12, 2016


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.

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