Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma
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ABSTRACT:
SUBMITTER: Shinhmar S
PROVIDER: S-EPMC11204349 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:BackgroundColon cancer is a common malignancy of the digestive tract. The search for effective drugs to treat colon cancer has become the focus of current researches. Tanshinone IIA (Tan IIA) is a fat-soluble component extracted from tanshinone, a traditional Chinese medicine. Tan IIA can modulate the occurrence and development of tumors, but its effect on autophagy in colon cancer cells has not been reported.MethodsTwo types of colon cancer cell lines were selected and different concentrations of Tan IIA were used to treat cells at different time points. Cell Counting Kit-8 assay (CCK-8) was used to detect the effect of Tan IIA on cell proliferation; transmission electron microscopy was used to observe the formation of autophagosomes; reverse transcription-polymerase chain reaction (RT-qPCR) and western blot were used to detect the expression of autophagy related genes and proteins. Cell transfection was used to interfere with MEK (mitogen-activated extracellular signal-regulated kinase) expression, and RT-qPCR and western blot were used to detect the expression of MEK/ERK/mTOR pathway-related proteins.ResultsTan IIA resulted in a significant reduction in the viability of the two kinds of colon cancer cells. The number of autophagosomes increased significantly after the treatment of Tan IIA into these cells. Addition of autophagy inhibitor 3-MA (3-Methyladenine) improved the increase of autophagosomes in cells induced by Tan IIA. At the same time, Tan IIA induced the expression of autophagy-related proteins in the two colon cancer cell lines. When Tan IIA induced autophagy in colon cancer cells, the expression of MEK/ERK/mTOR pathway-related proteins increased significantly. After interfering with the expression of MEK, the expression of autophagy decreased significantly, indicating that Tan IIA promoted autophagy of colon cancer cells through MEK/ERK/mTOR pathway.ConclusionsTan IIA stimulates autophagy in colon cancer cells through MEK/ERK/mTOR pathway, hence inhibiting the growth of colon cancer cells.
| S-EPMC8797932 | biostudies-literature
Project description:Tanshinone IIA on Gut Microbiome in Diabetes-induced Cognitive Dysfunction
| PRJEB51712 | ENA
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
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
Project description:Oxidative stress in retinal pigment epithelium (RPE) is considered to be a major contributor to the development and progression of age-related macular degeneration (AMD). Previous investigations have shown that sodium tanshinone IIA sulfonate (STS) can alleviate oxidative stress in haemorrhagic shock-induced organ damage and cigarette smoke-induced chronic obstructive pulmonary disease in mice. However, whether STS has a protective effect in ARPE-19 cells under oxidative stress and its exact mechanisms have not yet been fully elucidated. In the present study, we utilized H2O2 to establish an oxidative stress environment. Our findings show that STS activated the PI3K/AKT/mTOR pathway to inhibit autophagy and diminished the expression of the autophagic proteins Beclin 1, ATG3, ATG7 and ATG9 in ARPE-19 cells under oxidative stress. Detection of the intrinsic apoptosis-related factors BAX, mitochondrial membrane potential (MMP), caspase-9, caspase-3 and BCL-2, as well as the extrinsic apoptosis-related factors c-FLIP, v-FLIP and caspase-8, confirmed that STS inhibited the intrinsic and extrinsic apoptotic pathways, and attenuated apoptosis in ARPE-19 cells under oxidative stress conditions. These findings shed new light on the protective effects of STS in ARPE-19 cells and its mechanisms under oxidative stress to provide novel and promising therapeutic strategies for AMD.
| S-EPMC6181947 | biostudies-literature
Project description:Tanshinone IIA (TIIA) is a diterpenoid naphthoquinone isolated from the herb Salvia miltiorrhiza with antitumor effects manifested at multiple levels that are mechanistically obscure. In our previous studies, we illustrated that TIIA treatment triggered apoptosis in human osteosarcoma 143B cells both in vitro and in vivo, accompanied with mitochondrial dysfunction. Importantly, the overall survival rate of patients with osteosarcoma who were randomly recruited to S. miltiorrhiza treatment was significantly higher than those without. Pursuing this observation, we evaluated the potential effect of TIIA on autophagy induction in osteosarcoma both in vivo and in vitro. We discovered that TIIA inhibited osteosarcoma cell survival through class I PI3K and Akt signaling pathways. In contrast, expression of class III PI3K required in the early stages of autophagosome generation was predominantly enhanced by TIIA treatment. Our study indicated that treatment of TIIA effectively induced autophagy in human osteosarcoma cells, which contributed to the blockade of anchorage-independent growth of osteosarcoma cells and ameliorated tumor progression in NOD/SCID mice. We demonstrated that TIIA-mediated autophagy occurred in a sestrin 2 (SESN2)-dependent but not Beclin 1-dependent manner. In addition, we defined the activation of HGK (MAP4K4 or mitogen-activated protein kinase kinase kinase kinase)/SAPK/JNK1/Jun kinase pathways in upregulating transcription of SESN2, in which TIIA triggered HGK/JNK1-dependent Jun activation and led to increased Jun recruitment to AP-1-binding site in the SESN2 promoter region. Our results offer novel mechanistic insight into how TIIA inhibits osteosarcoma growth and suggest TIIA as a promising therapeutic agent for the treatment of cancer.
| S-EPMC6158215 | biostudies-literature
Project description:Clinical use of the anti-cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced cardiotoxicity (DIC). Prior studies have indicated that Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well-known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC-51-like kinase 1 (ULK1)-Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.
| S-EPMC6679133 | biostudies-literature
Project description:BackgroundTanshinone II A is an effective component extracted from Salvia miltiorrhiza and the roles of Tanshinone IIA in regulating the stemness of tumor cells remain unclear. This work aims to explore the roles and underlying mechanisms of Tanshinone IIA in breast cancer stemness.MethodsIn vitro mammary spheroid formation, flow cytometry assay on CD24-/CD44+ sub-population, ALDH activity detection, cell viability assay and western blot analysis, and in vivo tumor-initiating analysis were performed to examine the effects of Tanshinone IIA on the stemness of breast cancer cells. MiRNAs-based transcriptome sequencing and data analysis, online dataset analysis, luciferase reporter assay combined with rescuing experiments were constructed to explore the underlying mechanisms.ResultsTanshinone IIA attenuated the stemness of breast cancer cells, evident by downregulating the expression of stemness markers, hindering the capacity of spheroid formation, decreasing the CD24-/CD44+ sub-population in a concentration-dependent manner and reducing the tumor-initiating ability of breast cancer cells. Additionally, Tanshinone IIA enhanced adriamycin sensitivity and attenuated adriamycin resistance of breast cancer cells. Combined with miRNAs-based transcriptome sequencing assay, it was found that Tanshinone IIA downregulated miR-125b level and upregulated its target gene STARD13 (StAR-related lipid transfer protein 13) level, thus inactivating the miR-125b/STARD13 axis, which had been previously confirmed to promote breast cancer progression. Notably, miR-125b overexpression enhanced the stemness of breast cancer cells, and miR-125b overexpression or STARD13 knockdown impaired the inhibitory effects of Tanshinone IIA on the stemness of breast cancer cells.ConclusionsTanshinone IIA could attenuate the stemness of breast cancer cells via targeting the miR-125b/STARD13 axis.
| S-EPMC8781032 | biostudies-literature
Project description:Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.
| S-EPMC8598375 | biostudies-literature
Project description:Tanshinone IIA (Tan IIA) possesses potent anti-atherogenic function, however, the underlying pharmacological mechanism remains incompletely understood. Previous studies suggest that oxidized LDL (oxLDL)-induced NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome activation in macrophages plays a vital role in atherogenesis. Whether the anti-atherogenic effect of Tan IIA relies on the inhibition of the NLRP3 inflammasome has not been investigated before. In this study, we found that Tan IIA treatment of high-fat diet fed ApoE-/- mice significantly attenuated NLRP3 inflammasome activation in vivo. Consistently, Tan IIA also potently inhibited oxLDL-induced NLRP3 inflammasome activation in mouse macrophages. Mechanically, Tan IIA inhibited NF-κB activation to downregulate pro-interleukin (IL) -1β and NLRP3 expression, and decreased oxLDL-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) and cluster of differentiation 36 (CD36), thereby attenuating oxLDL cellular uptake and subsequent induction of mitochondrial and lysosomal damage - events that promote the NLRP3 inflammasome assembly. Through regulating both the inflammasome 'priming' and 'activation' steps, Tan IIA potently inhibited oxLDL-induced NLRP3 inflammasome activation, thereby ameliorating atherogenesis.
| S-EPMC7835056 | biostudies-literature