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Tanshinone IIA mediates SMAD7-YAP interaction to inhibit liver cancer growth by inactivating the transforming growth factor beta signaling pathway.

ABSTRACT: Tanshinone IIA (TanIIA)-an active constituent of Salvia miltiorrhiza, a traditional Chinese medicinal plant-is known to have blood circulation promotion and anti-tumor properties. Tan IIA can induce tumor cell death and inhibit tumor growth. However, the functions and underling molecular mechanisms of Tan IIA action on human liver cancer cells remain poorly understand. In this study, we found that Tanshinone IIA mediates SMAD7-YAP interaction to induce liver cancer cell apoptosis and inhibit cell growth and migration by inactivating the transforming growth factor beta (TGF-?) signaling pathway. Our findings showed that the Tan IIA-SMAD7-YAP regulatory network might be an effective strategy for liver cancer treatment.

SUBMITTER: Ma L

PROVIDER: S-EPMC6874425 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Tanshinone IIA mediates SMAD7-YAP interaction to inhibit liver cancer growth by inactivating the transforming growth factor beta signaling pathway.

Ma Lifang L Jiang Hongyuan H Xu Xin X Zhang Congcong C Niu Yongjie Y Wang Zhixian Z Tao Yuquan Y Li Yan Y Cai Feng F Zhang Xiao X Wang Xinghe X Yu Yongchun Y

Aging 20191111 21

Tanshinone IIA (TanIIA)-an active constituent of <i>Salvia miltiorrhiza</i>, a traditional Chinese medicinal plant-is known to have blood circulation promotion and anti-tumor properties. Tan IIA can induce tumor cell death and inhibit tumor growth. However, the functions and underling molecular mechanisms of Tan IIA action on human liver cancer cells remain poorly understand. In this study, we found that Tanshinone IIA mediates SMAD7-YAP interaction to induce liver cancer cell apoptosis and inhi ...[more]

PMID: 31711043

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Tanshinone IIA attenuates osteoclastogenesis in ovariectomized mice by inactivating NF-kB and Akt signaling pathways.

Project description:Osteoporosis is a common disease associated with age and menopausal status. Postmenopausal osteoporosis is the most common type of primary osteoporosis and is accompanied by increased risk of osteoporotic fracture. Natural and herbal compounds have long been used to prevent and treat many human diseases. Here, we demonstrated that tanshinone IIA prevented ovariectomy-induced bone loss in an in vivo mouse model that closely mimics osteoporosis. In addition, we found that tanshinone IIA inhibited the receptor activator of nuclear factor NF-κB ligand (RANKL)-induced osteoclast differentiation and osteoclastogenesis in vitro. Tanshinone IIA treatment also abrogated RANKL-induced activation of the NF-κB pathway, PI3-kinase/Akt signaling, and the mitogen-activated protein kinase (MAPK) pathways, including nuclear translocation of NF-κB p65 and phosphorylation of IκB, extracellular signal-regulated kinase (ERK), p38, and Akt. Inactivation of these pathways resulted in deceased expression of osteoclastogenesis-related markers. These results suggest that tanshinone IIA, a natural drug, has the potential to treat and prevent bone loss diseases, including postmenopausal osteoporosis.

| S-EPMC5992540 | biostudies-literature

Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis.

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| S-EPMC548008 | biostudies-other

Smad7 inhibits transforming growth factor-beta family type i receptors through two distinct modes of interaction.

Project description:The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-? (TGF-?) family signaling. I-Smads inhibit TGF-? family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. However, how I-Smads interact with type I receptors is not well understood. In the present study, we found that Smad7 has two modes of interaction with type I receptors. One is through a three-finger-like structure in the MH2 domain, consisting of residues 331-361, 379-387, and the L3 loop. The other is through a basic groove in the MH2 domain (Mochizuki, T., Miyazaki, H., Hara, T., Furuya, T., Imamura, T., Watabe, T., and Miyazono, K. (2004) J. Biol. Chem. 279, 31568-31574). We also found that Smad6 principally utilizes a basic groove in the MH2 domain for interaction with type I receptors. Smad7 thus has an additional mode of interaction with TGF-? family type I receptors not possessed by Smad6, which may play roles in mediating the inhibitory effects unique to Smad7.

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Tanshinone IIA Inhibits Osteosarcoma Growth through a Src Kinase-Dependent Mechanism.

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| S-EPMC8376467 | biostudies-literature

Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β)/Smad Signaling.

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| S-EPMC4697173 | biostudies-literature

Tanshinone IIA suppresses ovarian cancer growth through inhibiting malignant properties and angiogenesis.

Project description:BackgroundIn Chinese herbal medicine, Tanshinone IIA (Tan-IIA) is one of the main compounds extracted from Salvia miltiorrhiza Bunge. Tan-IIA has been demonstrated to inhibit the growth of various tumors. However, the detailed molecular and cellular mechanisms of the antitumor effect of Tan-IIA have yet to be fully illuminated.MethodsA2780 and ID-8 were treated with 0, 1.2, 2.4, 4.8, or 9.6 µg/mL Tan-IIA for 24 hours. Cell counting Kit-8 assay and EdU staining were used to evaluate cell proliferation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometry were performed to analyze apoptosis. Western blot was carried out to determine the protein levels. Flow cytometry was used for cell cycle analysis. The levels of mRNA expression were analyzed by real-time polymerase chain reaction. The anti-tumor effect of Tan-IIA was observed in a tumor-bearing mouse model.ResultsTan-IIA inhibited the proliferation of ovarian cancer cells in a dose-dependent manner by inducing G2/M phase arrest. It also down-regulated B-cell lymphoma 2 (Bcl-2) and up-regulated Bcl-2-associated X protein (Bax) in ovarian cancer cells to induce apoptosis, and suppressed cell migration by inhibiting focal adhesion kinase phosphorylation. Tan-IIA significantly reduced vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX2) mRNA expression in ovarian cancer cells. In vivo, Tan-IIA significantly inhibited tumor growth by inducing apoptosis and promoting anti-angiogenesis.ConclusionsThe results of this study shed light on the molecular and cellular mechanisms for the antitumor effect of Tan-IIA.

| S-EPMC7661888 | biostudies-literature

Tanshinone IIA on microbiome

Project description:Tanshinone IIA on Gut Microbiome in Diabetes-induced Cognitive Dysfunction

| PRJEB51712 | ENA

Transforming Growth Factor-β1/Smad7 in Intestinal Immunity, Inflammation, and Cancer.

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| S-EPMC6019438 | biostudies-literature

Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance.

Project description:Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.

| S-EPMC7862432 | biostudies-literature

Targeting survivin with Tanshinone IIA inhibits tumor growth and overcomes chemoresistance in colorectal cancer.

Project description:The inhibitor of apoptosis protein survivin has a critical regulatory role in carcinogenesis and treatment tolerance in colorectal cancer (CRC). However, the targeted drugs for survivin protein are extremely limited. In the present research, we discovered that Tanshinone IIA (Tan IIA) played a dual regulatory role in inhibiting tumorigenesis and reversing 5-Fu tolerance via modulating the expression and phosphorylation of survivin in CRC cells. Mechanistically, Tan IIA suppressed the Akt/WEE1/CDK1 signaling pathway, which led to the downregulation of survivin Thr34 phosphorylation and destruction of the interaction between USP1 and survivin to promote survivin ubiquitination and degradation. Furthermore, Tan IIA significantly facilitated chemoresistant CRC cells to 5-Fu sensitivity. These results revealed that Tan IIA possessed a strong antitumor activity against CRC cells and could act as an up-and-coming agent for treating CRC and overcoming chemotherapy resistance.

| S-EPMC10520088 | biostudies-literature

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