Abstract 4784
Background
Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis and promotes cancer cell migration and invasion. Transforming growth factor-beta (TGF-β), a well-known inducer of fibroblast proliferation, plays a crucial role in cancerous EMT via regulating E-cadherin or vimentin expression through TGF-β/Smad signaling. Tranilast is an anti-allergic drug clinically used for the treatment of keloids and hypertrophic scars to inhibit tissue fibrosis. We investigated whether trainlast could inhibit TGF-β-induced EMT in non-small cell lung cancer (NSCLC) cell lines.
Methods
We used A549 and PC14 NSCLC cell lines which are epithelial type cultured under normal conditions, but changes their phenotype into mesenchymal type with TGF-β stimulation. Western blottings were applied to examine epithelial or mesenchymal markers, and signal transductions of TGF-β/Smad pathway in these cell lines exposed to tranilast. To downregulate Smad signaling, siRNA methods were applied. Next, to investigate the capability of in vitro invasion, matrigel invasion assays were performed in which TGF-β was used as a chemoattractant. To develop orthotopic in vivo cancer models, A549 cells mixed with matrigel were injected into left lung of nude mice. Subsequently, mice were treated with or without tranilast for one month, then, the number of micrometastasis in both lungs were counted and compared between the two groups.
Results
In mesenchymal phenotype of A549 and PC14 stimulated with TGF-β, tranilast reinstated EMT via suppressing Smad4. The downregulation of Smad4 by siRNA methods also induced the recovery of EMT in these cell lines, resulting in the inhibition of in vitro invasion. The number of tumor spread through air space (STAS) in lung parenchyma was more suppressed in the tranilast administerd mice group.
Conclusions
Tranilast suppressed TGF-β-induced EMT via the downregulation of Smad4 resulting in the inhibition of in vitro and in vivo invasion/metastasis in lung cancer cell lines.
Clinical trial identification
Legal entity responsible for the study
Kyoto University Graduate School, Thoracic Surgery.
Funding
Has not received any funding.
Editorial Acknowledgement
Kissei Pharmaceutical Co., Ltd.
Disclosure
All authors have declared no conflicts of interest.
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