IM-412 inhibits the invasion of human breast carcinoma cells by blocking FGFR-mediated signaling.
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.
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Seung-Youn
SY
Jung
Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Jae Youn
JY
Yi
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Mi-Hyoung
MH
Kim
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Kyung-Hee
KH
Song
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Seong-Mook
SM
Kang
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Jiyeon
J
Ahn
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Sang-Gu
SG
Hwang
Center for Development and Commercialization of Anti-Cancer Therapeutics, Asan Medical Center, Seoul, Republic of Korea.
Ky-Youb
KY
Nam
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Jie-Young
JY
Song
D014408:Biomarkers, Tumor / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology
C552121:3-(2-chlorobenzyl)-1,7-dimethyl-1H-imidazo(2,1-f)purine-2,4(3H,8H)-dione; D014408:Biomarkers, Tumor; D007093:Imidazoles; D011687:Purines; D016212:Transforming Growth Factor beta; C496348:FGFR1 protein, human; C496365:FGFR3 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3