TGF-β1/PTEN/PI3K signaling plays a critical role in the anti-proliferation effect of tetrandrine in human colon cancer cells

Abstract

The diagnosis and treatment for colon cancer have been greatly developed, but the prognosis remains unsatisfactory. There is still a great clinical need to explore new efficacious drugs for colon cancer treatment. Tetrandrine (Tet) is a bis-benzylisoquinoline alkaloid. It has been shown that Tet may be a potential candidate for cancer treatment, but the explicit mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Tet in human colon cancer cells and dissected the possible mechanism. With cell viability assay and flow cytometry analysis, we confirmed that Tet can effectively inhibit the proliferation and induce apoptosis in HCT116 cells. Mechanically, we found that Tet greatly increases the mRNA and protein level of TGF-β1 in HCT116 cells. Exogenous TGF-β1 enhances the anti-proliferation and apoptosis inducing effect of Tet in HCT116 cells, which has been partly reversed by TGF-β1 inhibitor. Tet decreases the phosphorylation of Akt1/2/3 in HCT116 cells. This effect can be enhanced by exogenous TGF-β1, but partly reversed by TGF-β1 inhibitor. Tet exhibits no effect on total level of PTEN, but decreases the phosphorylation of PTEN; exogenous TGF-β1 enhances the effect of Tet on decreasing the phosphorylation of PTEN, which was partly reversed by TGF-β1 inhibitor. Our findings suggested that Tet may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating TGF-β1 to decrease the phosphorylation of PTEN.

TGFβ1 induces bone formation from BMP9-activated Bone Mesenchymal Stem Cells, with possible involvement of non-canonical pathways

“…These findings are consistent with our observation of significantly increased expression levels of STAT6 and STAT5B as a result of TGFβ1 activation. It is well established that the activation of the PI3K-Akt axis by TGFβ1 can trigger a wide range of metabolic and cellular effects in different cell types [48][49][50][51]. Consistent with our finding, the PI3K-Akt cascade has long been considered as one of the most significant Smad-independent regulatory route for MSC osteogenesis [52].…”

Tetrandrine inhibits proliferation of colon cancer cells by BMP9/ PTEN/ PI3K/AKT signaling

“…According to the above data, Tet can effectively suppress the growth and induce apoptosis in SW620 cells, so we next explored the underlying molecular mechanisms. Based on the reported that BMP9 is involved in the development of colon cancer, 26 we further explore BMP9 endogenous protein level in LoVo, HCT116, SW480, SW620, and FHC cell lines. Results showed that BMP9 mRNA level in cancer cells is much higher than that of FCH cells ( Fig.…”

“…In terms of mechanism, it was reported that some critical molecules or signaling pathways are associated with the pathogenesis of colon cancer, such as Wnt, EMT and TGF-β. 14 , 15 , 26 However, the explicit mechanism keeps unclear yet.…”

“… 34 Furthermore, it was reported that Tet reduced the level of p-Akt1/2/3, which may be impacted by PTEN in HCT116 cells. 26 …”

Tetrandrine Inhibits Epithelial-Mesenchymal Transition in IL-6-Induced HCT116 Human Colorectal Cancer Cells

“…Tetrandrine caused cell cycle arrest 45 and inhibited proliferation in colon cancer cells in vitro. [46][47][48] In addition, tetrandrine induced apoptosis in vitro and in vivo. 49,50 A previous study reported that tetrandrine inhibited the metastasis of CRC; 51 however, to the best of our knowledge, the molecular mechanism has yet to be investigated.…”