Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction

Ma, Ya‐Hui; Zhang, Jun; Zhang, Qi; Chen, Ping; Song, Jianliang; Yu, Shunji; Liu, Hui; Liu, Fuchen; Song, Chunhua; Yang, Dongqin; Liu, Jie

doi:10.1016/j.bbrc.2014.04.007

Cited by 48 publications

(40 citation statements)

References 21 publications

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“…A number of studies have reported that adenosine induces apoptosis via the activation of caspase-3 and caspase-9, and the subsequent stimulation of mitochondrial reactive oxygen species production in BEL-7404 human liver cancer cells (23,24). Adenosine has also been shown to downregulate expression of the anti-apoptotic factor Bcl-xl, and upregulate the expression of the pro-apoptotic factor BH3 interacting-domain death agonist via the A 2a adenosine receptor, thereby disrupting mitochondrial membrane potentials to facilitate the efflux of cytochrome c from the mitochondria into the cytosol to activate caspase-9 and -3 in human liver cancer HepG2 cells (25).…”

Section: Discussionmentioning

confidence: 99%

Adenosine induces intrinsic apoptosis via the PI3K/Akt/mTOR signaling pathway in human pharyngeal squamous carcinoma FaDu cells

et al. 2018

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Adenosine has been identified to occur abundantly intra-and extracellularly, and to exert diverse biological functions, including the suppression of cell proliferation and the induction of apoptosis. Adenosine has been reported to induce apoptosis in several cancer cell lines; however, to the best of our knowledge, the effect of adenosine on head and neck cancer cells has not been investigated. Therefore, the purpose of the present study was to evaluate whether adenosine exerts any anticancer effect via induction of apoptosis in human pharyngeal squamous carcinoma FaDu cells. An MTT assay demonstrated that adenosine-treated FaDu cells inhibited a dose-dependent rate of cell growth, whereas human oral keratinocytes cells were unaffected by adenosine treatment. In addition, A and A adenosine receptor mRNA was detected in FaDu cells by reverse transcription-polymerase chain reaction, and adenosine-induced FaDu cell death was significantly suppressed by treatment with ATL-444, an antagonist of these receptors. Furthermore, adenosine-induced cell growth inhibition was exerted via apoptosis, as confirmed by the analysis of DNA fragmentation, Hoechst nuclear staining and flow cytometry with Annexin V-fluorescein isothiocyanate and propidium iodide staining. Adenosine was also demonstrated to induce an increase in Bcl-associated X expression, a decrease in B-cell lymphoma 2 expression, the release of cytochrome c from mitochondria, and the activation of caspase-3, -9 and poly(ADP-ribose) polymerase in FaDu cells. Finally, phosphoinositide 3-kinase (PI3K), RAC serine/threonine-protein kinase (Akt) and mechanistic target of rapamycin (mTOR) phosphorylation was found to be significantly inhibited in adenosine-treated FaDu cells, as was phosphorylation of the mTOR downregulators, S6 kinase β1, eukaryotic translation initiation factor 4E-binding protein 1, and eukaryotic translation initiation factor 4 γ1. Taken together, these results indicate that adenosine induces apoptosis via the mitochondrial intrinsic pathway, and activates caspase-3 and -9 activity via the PI3K/Akt/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Adenosine induces intrinsic apoptosis via the PI3K/Akt/mTOR signaling pathway in human pharyngeal squamous carcinoma FaDu cells

et al. 2018

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“…ROS can induce apoptosis in many different cell systems [24–26]. BITC-induced apoptosis via ROS-modulated mitochondria pathways in A375.S2 cells [16].…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Deacetylase HDAC6 Inhibits the Melanoma Cell Line A375.S2 Growth through ROS-Dependent Mitochondrial Pathway

Bai

Lei

et al. 2015

PLoS ONE

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Previous studies have shown that histone deacetylase 6 (HDAC6) plays critical roles in many cellular processes related to cancer. However, its biological roles in the development of melanoma remain unexplored. Our aim was to investigate whether HDAC6 has a biological role in human melanoma development and to understand its underlying mechanism. In the present study, HDAC6 expression was up-regulated in melanoma tissues and cell lines. Knockdown of HDAC6 significantly inhibited the proliferation and colony formation ability of A375.S2 cells, promoted cell arrest at G0/G1 phase and apoptosis. Additionally, western blotting assay showed that HDAC6 silencing suppressed Bcl-2 level and enhanced Bax level, then activated caspase-9 and caspase-3, and further activated the release of cytochrome c from mitochondria to cytoplasm, finally induced cell apoptosis involving the mitochondrial pathway. Knockdown of HDAC6 triggered a significant generation of ROS and disruption of mitochondrial membrane potential (MMP). Furthermore, ROS inhibitor, NAC reduced HDAC6 siRNA-induced ROS production, and blocked HDAC6 siRNA-induced loss of MMP and apoptosis. NAC also significantly blocked HDAC6 siRNA-induced mtDNA copy number decrease and mitochondrial biogenesis and degradation imbalance. In conclusion, the results showed that knockdown of HDAC6 induced apoptosis in human melanoma A375.S2 cells through a ROS-dependent mitochondrial pathway.

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“…Along with the progression of HCC, ROS overproduction or long-lasting oxidative stress-responses would tend to induce cell death or prevent cancer development in HCC [1, 5]. Therefore, modulating homeostasis of ROS or oxidative stress-responses has become an important therapeutic strategy for HCC [5, 6]. Accumulative evidences support that oxidants have therapeutic effects in cancer treatment and the underlying mechanisms have been well studied [5, 7-11].…”

Section: Introductionmentioning

confidence: 99%

Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP

et al. 2015

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Hepatocellular carcinomas (HCC) are highly malignant and aggressive tumors lack of effective therapeutic drugs. Piperlongumine (PL), a natural product isolated from longer pepper plants, is recently identified as a potent cytotoxic compound highly selective to cancer cells. Here, we reported that PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway. PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 μM while PL at much lower concentrations only suppressed HCC cell migration/invasion. PL selectively elevated reactive oxygen species (ROS) in HCC cells, which activated or up-regulated downstream PERK/Ire 1α/Grp78, p38/JNK/Erk and CHOP subsequently. Administration of antioxidants completely abolished PL's effects on cell death and migration/invasion. However, pharmacological inhibition of ER stress-responses or MAPKs signaling pathways with corresponding specific inhibitors only reversed PL's effect on cell migration/invasion but not on cell death. Consistently, knocking-down of CHOP by RNA interference only reversed PL-suppressed HCC cell migration. Finally, PL significantly suppressed HCC development and activated the ER-MAPKs-CHOP signaling pathway in HCC xenografts in vivo. Taken together, PL selectively killed HCC cells and preferentially inhibited HCC cell migration/invasion via ROS-ER-MAPKs-CHOP axis, suggesting a novel therapeutic strategy for the highly malignant and aggressive HCC clinically.

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Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction

Cited by 48 publications

References 21 publications

Adenosine induces intrinsic apoptosis via the PI3K/Akt/mTOR signaling pathway in human pharyngeal squamous carcinoma FaDu cells

Adenosine induces intrinsic apoptosis via the PI3K/Akt/mTOR signaling pathway in human pharyngeal squamous carcinoma FaDu cells

Down-Regulation of Deacetylase HDAC6 Inhibits the Melanoma Cell Line A375.S2 Growth through ROS-Dependent Mitochondrial Pathway

Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP

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