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Estrogen receptor ? induces autophagy of osteosarcoma through the mTOR signaling pathway.

ABSTRACT: BACKGROUND:Estrogen receptor beta (ER?) was considered as a tumor-inhibiting factor in estrogen-sensitive malignant tumors. In this study, we intended to investigate whether ER? was involved in inducing autophagy in osteosarcoma. METHODS:This is an experimental study. The associations between ER? and autophagy were detected in osteosarcoma U2-OS cells which were treated with E2, E2 + 2,3-Bis (4-hydroxyphenyl) propionitrile (DPN, ER? agonists), E2 + DPN + water, E2 + DPN + 3-Methyladenine (3-MA, autophagy inhibitor), respectively. Cell viability and death were detected using cell counting kit 8 assay and flow cytometry, respectively. In addition, the expression of autophagy marker LC3II/I, sequestosome 1 (P62), mammalian target of rapamycin (mTOR), and phosphorylated-mTOR (p-mTOR) was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. RESULTS:Cell viability was significantly decreased with DPN treatment, while was reversed with 3-MA treatment. DPN treatment decreased living cells proportion and increased cell apoptosis proportion, while 3-MA treatment reversed those changes. However, there were significant differences between the E2 group and the E2 + DPN + 3-MA group for the living cell proportion and cell apoptosis proportion, suggesting apoptosis and autophagy all were induced. In addition, DPN treatment upregulated the LC3II/I expression level and downregulated P62 and mTOR (mRNA level) and p-mTOR (protein level) expression levels. CONCLUSION:ER? inhibited the cell viability and mediated cell death by inducing apoptosis and autophagy in osteosarcoma. ER?-induced autophagy in osteosarcoma was associated with downregulating the P62 expression level and inhibiting mTOR activation.

SUBMITTER: Yang Z

PROVIDER: S-EPMC7020596 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Estrogen receptor β induces autophagy of osteosarcoma through the mTOR signaling pathway.

Yang Zhengming Z Yu Wei W Liu Bing B Yang Minfei M Tao Huimin H

Journal of orthopaedic surgery and research 20200213 1

<h4>Background</h4>Estrogen receptor beta (ERβ) was considered as a tumor-inhibiting factor in estrogen-sensitive malignant tumors. In this study, we intended to investigate whether ERβ was involved in inducing autophagy in osteosarcoma.<h4>Methods</h4>This is an experimental study. The associations between ERβ and autophagy were detected in osteosarcoma U2-OS cells which were treated with E2, E2 + 2,3-Bis (4-hydroxyphenyl) propionitrile (DPN, ERβ agonists), E2 + DPN + water, E2 + DPN + 3-Methyl ...[more]

PMID: 32054506

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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:Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.

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Estrogen receptor ? induces autophagy of osteosarcoma through the mTOR signaling pathway.

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Estrogen receptor β induces autophagy of osteosarcoma through the mTOR signaling pathway.

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