Tanshinone IIA Inhibits Epithelial-Mesenchymal Transition in Bladder Cancer Cells via Modulation of STAT3-CCL2 Signaling

Abstract

Tanshinone IIA (Tan-IIA) is an extract from the widely used traditional Chinese medicine (TCM) Danshen (Salvia miltiorrhiza), and has been found to attenuate the proliferation of bladder cancer (BCa) cells (The IC50 were: 5637, 2.6 μg/mL; BFTC, 2 μg/mL; T24, 2.7 μg/mL, respectively.). However, the mechanism of the effect of Tan-IIA on migration inhibition of BCa cells remains unclear. This study investigates the anti-metastatic effect of Tan-IIA in human BCa cells and clarifies its molecular mechanism. Three human BCa cell lines, 5637, BFTC and T24, were used for subsequent experiments. Cell migration and invasion were evaluated by transwell assays. Real-time RT-PCR and western blotting were performed to detect epithelial-mesenchymal transition (EMT)-related gene expression. The enzymatic activity of matrix metalloproteinases (MMP) was evaluated by zymography assay. Tan-IIA inhibited the migration and invasion of human BCa cells. Tan-IIA suppressed both the protein expression and enzymatic activity of MMP-9/-2 in human BCa cells. Tan-IIA up-regulated the epithelial marker E-cadherin and down-regulated mesenchymal markers such as N-cadherin and Vimentin, along with transcription regulators such as Snail and Slug in BCa cells in a time- and dose-dependent manner. Mechanism dissection revealed that Tan-IIA-inhibited BCa cell invasion could function via suppressed chemokine (C-C motif) ligand 2 (CCL2) expression, which could be reversed by the addition of CCL2 recombinant protein. Furthermore, Tan-IIA could inhibit the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) (Tyr705), which cannot be restored by the CCL2 recombinant protein addition. These data implicated that Tan-IIA might suppress EMT on BCa cells through STAT3-CCL2 signaling inhibition. Tan-IIA inhibits EMT of BCa cells via modulation of STAT3-CCL2 signaling. Our findings suggest that Tan-IIA can serve as a potential anti-metastatic agent in BCa therapy.

Tanshinone IIA combined with cisplatin synergistically inhibits non‐small‐cell lung cancer in vitro and in vivo via down‐regulating the phosphatidylinositol 3‐kinase/Akt signalling pathway

“…However, there is no evidence at the cellular level or from animal models demonstrating such an effect of the combination of Tan IIA with DDP on NSCLC progression. The study presented herein indicates that the combination of Tan IIA with DDP diminishes It has been reported that Tan IIA inhibits the migration and invasion ability of bladder cancer cells (Huang, Chang, Liao, & Chiu, 2017) and Tan IIA combined with adriamycin inhibits migration and invasion ability in NSCLC (Xie et al, 2016). Our findings also showed that Tan IIA combined with DDP could inhibit the migration and invasion ability of A549 and PC9 cells in a synergistic manner.…”

“…It has been reported that Tan IIA inhibits the migration and invasion ability of bladder cancer cells (Huang, Chang, Liao, & Chiu, ) and Tan IIA combined with adriamycin inhibits migration and invasion ability in NSCLC (Xie et al, ). Our findings also showed that Tan IIA combined with DDP could inhibit the migration and invasion ability of A549 and PC9 cells in a synergistic manner.…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Tanshinone IIA is a major bioactive component from the famous medical herb Salvia miltiorrhiza that was reported to attenuate the proliferation of bladder cancer cells (Table ). Further study revealed that tanshinone IIA suppressed EMT in bladder cancer cells via the modulation of the STAT3‐CCL2 signaling pathway . In addition, tanshinone IIA blocked EMT by regulating the TGF‐β/Smad pathway in peritoneal fibrosis .…”

“…Further study revealed that tanshinone IIA suppressed EMT in bladder cancer cells via the modulation of the STAT3-CCL2 signaling pathway. 32 In addition, tanshinone IIA blocked EMT by regulating the TGF-β/Smad pathway in peritoneal fibrosis. 116 From these data, it was suggested that compounds that target EMT might have both antifibrotic and anticancer…”

SARI suppresses colitis‐associated cancer development by maintaining MCP‐1‐mediated tumour‐associated macrophage recruitment

“…Furthermore, STAT1 was also proved as the direct target of SARI in colon cancer cells, evidenced by Co-IP and IF staining, as indicated in intestinal epithelial cells. 18 Other transcriptional regulation factors of MCP-1, including NF-κB 30,31 and STAT3, 32,33 were up-regulated in colon tissues of SARI −/− mice in CAC, but demonstrated not to be the direct target of SARI in colon cancer cells. The inverse correlation between SARI and p-STAT1 was also observed in colon malignant tissues of patients, whereas SARI mRNA expression was positively correlated with STAT1 mRNA expression.…”