IM-412 inhibits the invasion of human breast carcinoma cells by blocking FGFR-mediated signaling

Jung,Seung-Youn; Yi,Jae  Youn; Kim,Mi-Hyoung; Song,Kyung-Hee; Kang,Seong-Mook; Ahn,Jiyeon; Hwang,Sang-Gu; Nam,Ky-Youb; Song,Jie-Young

doi:10.3892/or.2015.4249

IM-412 inhibits the invasion of human breast carcinoma cells by blocking FGFR-mediated signaling

Authors:
- Seung-Youn Jung
- Jae Youn Yi
- Mi-Hyoung Kim
- Kyung-Hee Song
- Seong-Mook Kang
- Jiyeon Ahn
- Sang-Gu Hwang
- Ky-Youb Nam
- Jie-Young Song
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Affiliations: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea, Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea, Center for Development and Commercialization of Anti-Cancer Therapeutics, Asan Medical Center, Seoul, Republic of Korea
Published online on: September 8, 2015 https://doi.org/10.3892/or.2015.4249
Pages: 2731-2737

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Abstract

Triple-negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis due to its epithelial‑to-mesenchymal transition (EMT) phenotype. Cancer patients often experience several detrimental effects of cancer treatment, such as chemoresistance, radioresistance and the maintenance of cancer stem cells due to EMT. Thus, EMT signaling is considered to be a valuable therapeutic target for cancer treatment, and its inhibition is being attempted as a new treatment option for TNBC patients. Previously, we showed that 3-(2-chlorobenzyl)-1,7-dimethyl-1H-imidazo[2,1-f]purine‑2,4(3H,8H)-dione (IM-412) inhibits transforming growth factor-β (TGF-β)-induced differentiation of human lung fibroblasts through both Smad-dependent and -independent pathways. In the present study, we examined the inhibitory effect of IM-412 on EMT pathways and invasiveness in TNBC cells since the TGF-β signaling pathway is a typical signaling pathway that functions in EMT. IM-412 not only potently suppressed the migration and invasion of MDA-MB-231 cells, but also lowered the expression of mesenchymal markers and EMT-activating transcription factors in these cells. IM-412 inhibited the activation of several signaling proteins, including Smad2/Smad3, p38MAPK, Akt and JNK, and it also attenuated the phosphorylation of FGFR1 and FGFR3. Collectively, our findings suggest that the synthetic compound IM-412 suppressed the EMT process in MDA-MB-231 cells and thereby effectively inhibited the migration and invasion of these cancer cells. Thus, IM-412 could serve as a novel therapeutic agent for malignant cancers.

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