Resveratrol inhibited the progression of human hepatocellular carcinoma by inducing autophagy via regulating p53 and the phosphoinositide�3‑kinase/protein kinase�B pathway

Zhang, Baichao; Yin, Xiaoning; Sui, Shaoguang

doi:10.3892/or.2018.6648

Cited by 53 publications

(42 citation statements)

References 32 publications

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“…Furthermore, studies have also suggested that RSV may initiate cell autophagy accompanied with or without apoptosis (17,18). A recent study demonstrated that RSV induced protective autophagy via the activation of SIRT1 in NSCLC (19), whereas other studies have shown that RSV-induced cell death is regulated through autophagy (20,21). Due to the limitations and contradictory results of previous studies, the mechanisms underlying the effects of RSV on NSCLC associated with PCD require further study to clarify the mechanisms using integrated analysis.…”

Section: Resveratrol Modulates the Apoptosis And Autophagic Death Of mentioning

confidence: 99%

Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation

Fan

Yang

et al. 2020

Int J Oncol

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Resveratrol (RSV) has been reported to exhibit cytotoxic activity in multiple types of malignant cells; however, the mechanisms underlying the antitumor effects of RSV in non-small-cell lung cancer (NSCLC) cells remain undetermined. Combining bioinformatics analysis with experimental validation, the present study aimed to examine the effects of RSV on the apoptosis and autophagy of A549 NSCLC cells, and to determine the potential underlying molecular mechanisms. Bioinformatics analysis was used to determine the differentially expressed genes (DEGs) and identify the enriched biological functions and pathways associated with these DEGs following RSV treatment. Cell viability was determined by MTT assay, and flow cytometry and TUNEL assay were used to evaluate cell apoptosis. Monodansylcadaverine staining combined with a transmission electron microscope were used to evaluate the extent of autophagy. The expression levels of apoptosis-, autophagy-, or pathway-associated molecular markers were measured by reverse transcription-quantitative PCR and/or western blot analysis. By bioinformatics analysis, a total of 1,031 DEGs were identified in the RSV-treated A549 cells, which were enriched in apoptosis-, or autophagy-related biological functions and the p53 signaling pathway. In validation experiments, RSV significantly reduced cell viability and initiated apoptosis, with an increase in the number of apoptotic cells; it also upregulated cleaved caspase-3 expression and Bax expression, and downregulated the Bcl-2 expression levels. Additionally, there was an increase in the accumulation of green dot-like structures, indicative of autophagic vesicles, observed under a fluorescence microscope, and an increase in the presence of autophagic vacuoles observed using a transmission electron microscope following RSV treatment. Furthermore, the expression levels of the autophagy-related proteins, LC3-II/LC3-I and Beclin-1, were increased and p62 expression was decreased. 3-methyladenine (3-MA), an inhibitor of autophagy, partially reversed the RSV-induced cytotoxic effects, but did not significantly alter the number of apoptotic cells. RSV elevated the p53 levels and decreased the phosphorylated (p-)Mdm2 and p-Akt levels. Pifithrin-α, an inhibitor of p53, partially reduced RSV-induced apoptosis and autophagy. On the whole, the results of the present study demonstrated that RSV initiates the apoptosis and autophagic death of A549 cells via the activation of the p53 signaling pathway, further highlighting the potential of RSV for the treatment of NSCLC.

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Section: Resveratrol Modulates the Apoptosis And Autophagic Death Of mentioning

confidence: 99%

Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation

Fan

Yang

et al. 2020

Int J Oncol

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“…Lin et al (78) reported that resveratrol can promote the recovery of the fatty liver and effectively decrease the incidence of HCC caused by the HBV X protein (HBX) in HBX transgenic mice via downregulating lipogenesis, promoting transient liver regeneration and stimulating antioxidant activity. Additionally, it has been demonstrated that resveratrol has therapeutic effects on HCC through the p53 (84), cell cycle (85)(86)(87). A previous study revealed that menadione kills tumor cells by influencing their redox cycle (45).…”

Section: Discussionmentioning

confidence: 99%

Identification of diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus‑associated early stage hepatocellular carcinoma based on RNA‑sequencing data

2020

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Primary liver cancer is a rapidly progressing neoplasm with high morbidity and mortality rates. The present study aimed to identify potential diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus (HBV)-associated early stage hepatocellular carcinoma (HCC). The gene expression profiles were extracted from the Gene Expression Omnibus database. Differentially expressed genes (DEGs), hub genes and the enrichment of signaling pathways were filtered out via a high-throughput sequencing method. The association between hub genes and the effects of the abnormal expression of hub genes on the rate of genetic variation, overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS) and disease-free survival (DSS) of patients with HCC, as well as pathological stage and grade, were analyzed using different databases. A total of 1,582 DEGs were identified. Gene Ontology analysis revealed that the DEGs were mainly involved in the 'oxidation-reduction process', 'steroid metabolic process', 'metabolic process' and 'fatty acid beta-oxidation'. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways revealed that the DEGs were mainly associated with 'metabolic pathways', 'PPAR signaling pathway', 'fatty acid degradation' and the 'cell cycle'. A total of 8 hub genes were extracted. Additionally, the abnormal expression levels of hub genes were closely associated with the OS, RFS, PFS and DSS of patients, the pathological stage and the grade. Furthermore, abnormal expression levels of the 8 hub genes were found in >30% of all samples. Several small molecular compounds that may reverse the altered DEGs were identified based on Connectivity Map analysis, including phenoxybenzamine, GW-8510, resveratrol, 0175029-0000 and daunorubicin. In conclusion, the dysfunction of fat metabolic pathways, the cell cycle, oxidation-reduction processes and viral carcinogenesis may serve critical roles in the occurrence of HBV-associated early stage HCC. The identified 8 hub genes may act as robust biomarkers for diagnosis and prognosis. Some small molecular compounds may be promising targeted agents against HBV-associated early stage HCC.

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“…Further, treatment with inhibitors, such as 3-MA and pifithrin-α, and insulin-like growth factor-1 (IGF-1) decreased the Beclin-1 expression, with the promotion of MHCC-97H cell survival. Altogether, resveratrol exhibited an anti-HCC effect by inducing autophagy through inhibiting PI3K/Akt and activating p53 [199].…”

Section: Stilbenesmentioning

confidence: 93%

“…Zhang et al [199] reported that resveratrol exerted antitumor effects in the HCC MHCC97-H cell line in a time-and concentration-dependent manner. Moreover, resveratrol treatment elevated the autophagy-related protein Beclin-1 and LC3 II/I ratio, whereas it decreased p62 expression.…”

Section: Stilbenesmentioning

confidence: 99%

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

Kiruthiga

Devi

Nabavi

et al. 2020

Cancers

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Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.

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Resveratrol inhibited the progression of human hepatocellular carcinoma by inducing autophagy via regulating p53 and the phosphoinositide�3‑kinase/protein kinase�B pathway

Cited by 53 publications

References 32 publications

Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation

Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation

Identification of diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus‑associated early stage hepatocellular carcinoma based on RNA‑sequencing data

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

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