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Atractylenolide II Suppresses Glycolysis and Induces Apoptosis by Blocking the PADI3-ERK Signaling Pathway in Endometrial Cancer Cells.

ABSTRACT: Atractylenolide II (AT-II), the major bioactive compound of Atractylodes macrocephala, exhibits anti-cancer activity against many types of tumors, but the roles and the potential mechanisms in endometrial cancer remain unclear. In the present study, AT-II treatment was found to significantly suppress RL95-2 and AN3CA cell proliferation and glycolysis, and induced their apoptosis by inactivating the ERK signaling pathway, accompanied by the changing expression of the glycolytic key enzymes and apoptotic-related proteins. Peptidyl arginine deiminase 3 (PADI3), as the candidate target gene of AT-II, was highly expressed in the endometrial cancer tissues and associated with a poor prognosis according to bioinformatics analysis. PADI3 knockdown inhibited proliferation and glycolysis in endometrial cancer cells and induced cell apoptosis. Furthermore, AT-II negatively regulated the expression of PADI3, and PADI3 overexpression reversed the effects of AT-II on endometrial cancer cells. Our findings suggested that the anti-cancer function of AT-II is associated with the suppression of glycolysis and induction of apoptosis by blocking the PADI3-ERK signaling pathway. Thus, AT-II represents a novel therapeutic target for endometrial cancer and targeting AT-II may serve as a potential strategy for the clinical therapy of endometrial cancer.

SUBMITTER: Tian S

PROVIDER: S-EPMC10934053 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Atractylenolide II Suppresses Glycolysis and Induces Apoptosis by Blocking the PADI3-ERK Signaling Pathway in Endometrial Cancer Cells.

Tian Shuang S Ren Lili L Liu Chao C Wang Zhe Z

Molecules (Basel, Switzerland) 20240221 5

Atractylenolide II (AT-II), the major bioactive compound of <i>Atractylodes macrocephala</i>, exhibits anti-cancer activity against many types of tumors, but the roles and the potential mechanisms in endometrial cancer remain unclear. In the present study, AT-II treatment was found to significantly suppress RL95-2 and AN3CA cell proliferation and glycolysis, and induced their apoptosis by inactivating the ERK signaling pathway, accompanied by the changing expression of the glycolytic key enzymes ...[more]

PMID: 38474453

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Project description:BackgroundMarsdenia tenacissima is an herb medicine which has been utilized to treat malignant diseases for decades. The M. tenacissima extract (MTE) shows significant anti-proliferation activity against non-small cell lung cancer (NSCLC) cells, but the underlying mechanisms remain unclear. In this study, we explored the potential anti-proliferation mechanisms of MTE in NSCLC cells in relation to apoptosis as well as autophagy, which are two critical forms to control cancer cell survival and death.MethodsThe proliferation of H1975 and A549 cells was evaluated by MTT assay. Cell apoptosis was assessed by Annexin V and PI staining, Caspase 3 expression and activity. Autophagy flux proteins were detected by Western blot with or without autophagy inducer and inhibitor. Endogenous LC3-II puncta and LysoTracker staining were monitored by confocal microscopy. The formation of autophagic vacuoles was measured by acridine orange staining. ERK is a crucial molecule to interplay with cell autophagy and apoptosis. The role of ERK on cell apoptosis and autophagy influenced by MTE was determined in the presence of MEK/ERK inhibitor U0126.ResultsThe significant growth inhibition and apoptosis induction were observed in MTE treated NSCLC cells. MTE induced cell apoptosis coexisted with elevated Caspase 3 activity. MTE also impaired autophagic flux by upregulated LC3-II and p62 expression. Autophagy inducer EBSS could not abolish the impaired autophagic flux by MTE, while it was augmented in the presence of autophagy inhibitor Baf A1. The autophagosome-lysosome fusion was blocked by MTE via affecting lysosome function as evidenced by decreased expression of LAMP1 and Cathepsin B. The molecule ERK became hyperactivated after MTE treatment, but the MEK/ERK inhibitor U0126 abrogated autophagy inhibition and apoptosis induction caused by MTE, suggested that ERK signaling pathways partially contributed to cell death caused by MTE.ConclusionOur results demonstrate that MTE caused apoptosis induction as well as autophagy inhibition in NSCLC cells. The activated ERK is partially associated with NSCLC apoptotic and autophagic cell death in response to MTE treatment. The present findings reveal new mechanisms for the anti-tumor activity of MTE against NSCLC.

Project description:BackgroundDcf1 has been demonstrated to play vital roles in many CNS diseases, it also has a destructive role on cell mitochondria in glioma cells and promotes the autophagy. Hitherto, it is unclear whether the viability of glioblastoma cells is affected by Dcf1, in particular Dcf1 possesses broad localization on different organelles, and the organelles interaction frequently implicated in cancer cells survival.MethodsSurgically excised WHO grade IV human glioblastoma tissues were collected and cells isolated for culturing. RT-PCR and DNA sequencing assay to estimate the abundance and mutation of Dcf1. iTRAQ sequencing and bioinformatic analysis were performed. Subsequently, immunoprecipitation assay to evaluate the degradation of HistoneH2A isomers by UBA52 ubiquitylation. Transmission electron microscopy (TEM) was applied to observe the structure change of mitochondria and autophagosome. Organelle isolated assay to determine the distribution of protein. Cell cycle and apoptosis were evaluated by flow cytometric assays.ResultsDcf1 was downregulated in WHO grade IV tumor without mutation, and overexpression of Dcf1 was found to significantly regulate glioblastoma cells. One hundred and seventy-six differentially expressed proteins were identified by iTRAQ sequencing. Furthermore, we confirmed that overexpression of Dcf1 destabilized the structure of the nucleosome via UBA52 ubiquitination to downregulate HistoneH2A.X but not macroH2A or HistoneH2A.Z, decreased the mitochondrial DNA copy number and inhibited the mitochondrial biogenesis, thus causing mitochondrial destruction and dysfunction in order to supply cellular energy and induce mitophagy preferentially but not apoptosis. Dcf1 also has disrupted the integrity of lysosomes to block autolysosome degradation and autophagy and to increase the release of Cathepsin B and D from lysosomes into cytosol. These proteins cleaved and activated BID to induce glioblastoma cells apoptosis.ConclusionsIn this study, we demonstrated that unmutated Dcf1 expression is negatively related to the malignancy of glioblastoma, Dcf1 overexpression causes nucleosomes destabilization, mitochondria destruction and dysfunction to induce mitophagy preferentially, and block autophagy by impairing lysosomes to induce apoptosis in glioblastoma.

Dataset Information

Atractylenolide II Suppresses Glycolysis and Induces Apoptosis by Blocking the PADI3-ERK Signaling Pathway in Endometrial Cancer Cells.

Publications

Atractylenolide II Suppresses Glycolysis and Induces Apoptosis by Blocking the PADI3-ERK Signaling Pathway in Endometrial Cancer Cells.

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