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A New TGF-β1 Inhibitor, CTI-82, Antagonizes Epithelial-Mesenchymal Transition through Inhibition of Phospho-SMAD2/3 and Phospho-ERK.

ABSTRACT: Transforming growth factor-β1 (TGF-β1) is highly expressed in the tumor microenvironment and known to play a multifunctional role in cancer progression. In addition, TGF-β1 promotes metastasis by inducing epithelial-mesenchymal transition (EMT) in a variety of tumors. Thus, inhibition of TGF-β1 is considered an important strategy in the treatment of cancer. In most tumors, TGF-β1 signal transduction exhibits modified or non-functional characteristics, and TGF-β1 inhibitors have various inhibitory effects on cancer cells. Currently, many studies are being conducted to develop TGF-β1 inhibitors from non-toxic natural compounds. We aimed to develop a new TGF-β1 inhibitor to suppress EMT in cancer cells. As a result, improved chalcone-like chain CTI-82 was identified, and its effect was confirmed in vitro. We showed that CTI-82 blocked TGF-β1-induced EMT by inhibiting the cell migration and metastasis of A549 lung cancer cells. In addition, CTI-82 reduced the TGF-β1-induced phosphorylation of SMAD2/3 and inhibited the expression of various EMT markers. Our results suggest that CTI-82 inhibits tumor growth, migration, and metastasis.

SUBMITTER: Jeong JH

PROVIDER: S-EPMC7408591 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A New TGF-β1 Inhibitor, CTI-82, Antagonizes Epithelial-Mesenchymal Transition through Inhibition of Phospho-SMAD2/3 and Phospho-ERK.

Jeong Ji-Hoon JH Kim Hyunhee H Park Seung-Ho SH Park Hayeon H Jeong Minseok M Kwak Sungmin S Sung Gi-Jun GJ Song Ji-Hye JH Na Younghwa Y Choi Kyung-Chul KC

Biology 20200628 7

Transforming growth factor-β1 (TGF-β1) is highly expressed in the tumor microenvironment and known to play a multifunctional role in cancer progression. In addition, TGF-β1 promotes metastasis by inducing epithelial-mesenchymal transition (EMT) in a variety of tumors. Thus, inhibition of TGF-β1 is considered an important strategy in the treatment of cancer. In most tumors, TGF-β1 signal transduction exhibits modified or non-functional characteristics, and TGF-β1 inhibitors have various inhibitor ...[more]

PMID: 32605257

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Project description:AimsThe study aims to explore new potential treatments for cervical cancer.BackgroundCervical cancer is the second most common cancer in women, causing >250,000 deaths worldwide. Patients with cervical cancer are mainly treated with platinum compounds, which often cause severe toxic reactions. Furthermore, the long-term use of platinum compounds can reduce the sensitivity of cancer cells to chemotherapy and increase the drug resistance of cervical cancer. Therefore, exploring new treatment options is meaningful for cervical cancer.ObjectiveThe present study was to investigate the effect of sildenafil on the growth and epithelial-tomesenchymal transition (EMT) of cervical cancer.MethodsHeLa and SiHa cells were treated with sildenafil for different durations. Cell viability, clonogenicity, wound healing, and Transwell assays were performed. The levels of transforming growth factor-β1 (TGF-β1), transforming growth factor-β type I receptor (TβRI), phosphorylated (p-) Smad2 and p-Smad3 in cervical cancer samples were measured. TGF-β1, Smad2 or Smad3 were overexpressed in HeLa cells, and we measured the expression of EMT marker proteins and the changes in cell viability, colony formation, etc. Finally, HeLa cells were used to establish a nude mouse xenograft model with sildenafil treatment. The survival rate of mice and the tumor size were recorded.ResultsHigh concentrations of sildenafil (1.0-2.0 μM) reduced cell viability, the number of HeLa and SiHa colonies, and the invasion/migration ability of HeLa and SiHa cells in a dose- and time-dependent manner. The expression of TGF-β1, TβRI, p-Smad2 and p-Smad3 was significantly enhanced in cervical cancer samples and cervical cancer cell lines. Sildenafil inhibited the expression of TGF-β1-induced EMT marker proteins (Snail, vimentin, Twist, E-cadherin and N-cadherin) and p-Smad2/3 in HeLa cells. Overexpression of TGF-β1, Smad2, and Smad3 reversed the effect of sildenafil on EMT, viability, colony formation, migration, and invasion ability of HeLa cells. In the in vivo study, sildenafil significantly increased mouse survival rates and suppressed xenograft growth.ConclusionSildenafil inhibits the proliferation, invasion ability, and EMT of human cervical cancer cells by regulating the TGF-β1/Smad2/3 pathway.

Dataset Information

A New TGF-β1 Inhibitor, CTI-82, Antagonizes Epithelial-Mesenchymal Transition through Inhibition of Phospho-SMAD2/3 and Phospho-ERK.

Publications

A New TGF-β1 Inhibitor, CTI-82, Antagonizes Epithelial-Mesenchymal Transition through Inhibition of Phospho-SMAD2/3 and Phospho-ERK.

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