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HGK-sestrin 2 signaling-mediated autophagy contributes to antitumor efficacy of Tanshinone IIA in human osteosarcoma cells.

ABSTRACT: 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.

SUBMITTER: Yen JH

PROVIDER: S-EPMC6158215 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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HGK-sestrin 2 signaling-mediated autophagy contributes to antitumor efficacy of Tanshinone IIA in human osteosarcoma cells.

Yen Jia-Hau JH Huang Sheng-Teng ST Huang Hung-Sen HS Fong Yi-Chin YC Wu Yi-Ying YY Chiang Jen-Huai JH Su Yuan-Chih YC

Cell death & disease 20180926 10

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 si ...[more]

PMID: 30258193

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Project description:Background Colon 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. Methods Two 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. Results Tan 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. Conclusions Tan IIA stimulates autophagy in colon cancer cells through MEK/ERK/mTOR pathway, hence inhibiting the growth of colon cancer cells.

Project description:Hypoxic ischemic encephalopathy (HIE) is the most common brain injury following hypoxia and/or ischemia caused by various factors during the perinatal period, resulting in detrimental neurological deficits in the nervous system. Tanshinone IIA (Tan‑IIA) is a potential agent for the treatment of cardiovascular and cerebrovascular diseases. In this study, the efficacy of Tan‑IIA was investigated in a newborn mouse model of HIE. The dynamic mechanism of Tan‑IIA was also investigated in the central nervous system of neonate mice. Intravenous injection of Tan‑IIA (5 mg/kg) was administered and changes in oxidative stress, inflammation and apoptosis‑associated proteins in neurons. Histology and immunohistochemistry was used to determine infarct volume and the number of damaged neurons by Fluoro‑Jade C staining. The effects of Tan‑IIA on mice with HIE were evaluated by body weight, brain water content, neurobehavioral tests and blood‑brain barrier permeability. The results demonstrated that the apoptosis rate was decreased following Tan‑IIA administration. Expression levels of pro‑apoptotic proteins, caspase‑3 and caspase‑9 and P53 were downregulated. Expression of Bcl‑2 anti‑apoptotic proteins was upregulated by Tan‑IIA treatment in neuro. Results also found that Tan‑IIA treatment decreased production of inflammatory cytokines such as interleukin‑1, tumor necrosis factor‑α, C‑X‑C motif chemokine 10, and chemokine (C‑C motif) ligand 12. Oxidative stress was also reduced by Tan‑IIA in neurons, as determined by the expression levels of superoxide dismutase, glutathione and catalase, and the production of reactive oxygen species. The results demonstrated that Tan‑IIA treatment reduced the infarct volume and the number of damaged neurons. Furthermore, body weight, brain water content and blood‑brain barrier permeability were markedly improved by Tan‑IIA treatment of newborn mice following HIE. Furthermore, the results indicated that Tan‑IIA decreased Toll‑like receptor‑4 (TLR‑4) and nuclear factor‑κB (NF‑κB) expression in neurons. TLR‑4 treatment of neuronal cell in vitro addition stimulated NF‑κB activity, and further enhanced the production of inflammatory cytokines and oxidative stress levels in neurons. In conclusion, these results suggest that Tan‑IIA treatment is beneficial for improvement of HIE through TLR‑4‑mediated NF‑κB signaling.

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HGK-sestrin 2 signaling-mediated autophagy contributes to antitumor efficacy of Tanshinone IIA in human osteosarcoma cells.

Publications

HGK-sestrin 2 signaling-mediated autophagy contributes to antitumor efficacy of Tanshinone IIA in human osteosarcoma cells.

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