Endoplasmic Reticulum Stress Plays a Pivotal Role in Cell Death Mediated by the Pan-Deacetylase Inhibitor Panobinostat in Human Hepatocellular Cancer Cells

Montalbano, Roberta; Waldegger, Petra; Quint, Karl; Jabari, Samir; Neureiter, Daniel; Illig, Romana; Ocker, Matthias; Fazio, Pietro Di

doi:10.1593/tlo.12271

Cited by 33 publications

(40 citation statements)

References 59 publications

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“…The autophagosomes, indicated in Figure 6 by white and black arrows, are clearly visible already after 6 h and the amount increased after 48 h, especially in Hep3B cells. In addition, as previously published, the micrographs show a disorganized endoplasmic reticulum with fragmented cisternae representing a clear sign of active autophagy [ 19 ]. Based on a previously published method [ 26 , 27 ], the number of vesicles was quantified from around 100 micrographs and divided into two subgroups: early autophagosomes characterized by a double membrane and late autophagosomes as fused with endo/lysosomal vesicles including subcellular particles (Figure 5C ).…”

Section: Resultssupporting

confidence: 78%

“…Additionally, panobinostat was shown to be able to induce the activation of non-canonical apoptotic pathways; its activity could promote cell demise via endoplasmic reticulum stress [ 18 , 19 ]. Furthermore, panobinostat is responsible for the up-regulation of hsa-let-7b, a tumor suppressor miRNA, and the consequent suppression of its target HMGA2 [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Panobinostat, in particular, already has been shown to promote cell death in a P53-independent manner, via induction of alternative apoptotic cell death mediated by endoplasmic reticulum (ER)-stress [ 18 , 19 ]. Additionally, panobinostat was found to induce the expression of the tumor suppressor hsa-let-7b and to prevent the expression of the oncogenic miR17-92 miRNAs cluster in liver cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy-related cell death by pan-histone deacetylase inhibition in liver cancer

et al. 2016

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Autophagy is a homeostatic, catabolic degradation process and cell fate essential regulatory mechanism. Protracted autophagy triggers cell death; its aberrant function is responsible for several malignancies. Panobinostat, a potent pan-deacetylase inhibitor, causes endoplasmic reticulum stress-induced cell death. The aim of this study was to investigate the role of autophagy in deacetylase inhibitor-triggered liver cancer cell death.HepG2 (p53wt) and Hep3B (p53 null) liver cancer cell lines were exposed to panobinostat. RT-qPCR and western blot confirmed autophagic factor modulation. Immuno-fluorescence, -precipitation and -histochemistry as well as transmission electron microscopy verified autophagosome formation. The cytotoxicity of panobinostat and autophagy modulators was detected using a real time cell viability assay.Panobinostat induced autophagy-related factor expression and aggregation. Map1LC3B and Beclin1 were significantly over-expressed in HepG2 xenografts in nude mice treated with panobinostat for 4 weeks. Subcellular distribution of Beclin1 increased with the appearance of autophagosomes-like aggregates. Cytosolic loss of p53, in HepG2, and p73, in Hep3B cells, and a corresponding gain of their nuclear level, together with modulation of DRAM1, were observed. Autophagosome aggregation was visible after 6 h of treatment. Treatment of cells stably expressing GFP-RFPtag Map1LC3B resulted in aggregation and a fluorescence switch, thus confirming autophagosome formation and maturation. Tamoxifen, an inducer of autophagy, caused only a block in cell proliferation; but in combination with panobinostat it resulted in cell death.Autophagy triggers cell demise in liver cancer. Its modulation by the combination of tamoxifen and panobinostat could be a new option for palliative treatment of hepatocellular carcinoma.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autophagy-related cell death by pan-histone deacetylase inhibition in liver cancer

et al. 2016

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“…The current study revealed that the IRE1α/XBP1 pathway may initiate downstream reactions. IRE1α activation can induce JNK phosphorylation and phosphorylated JNK can exert proapoptotic effects by activating caspase-12/4 and caspase-8 (7). Additionally, XBP1 is known to activate the transcription of CHOP (25), therefore XBP1 contributes to the induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate ER stress, dysfunction of the ER and the unfolded protein response was induced under adverse conditions, including metabolic and anaerobic stress, which disrupts the protein-folding function of the ER. Altered ER homeostasis results in an accumulation of unfolded or misfolded proteins, which ultimately leads to ER stress (6,7). The ER stress response activates cytotoxic mechanisms involving a number of regulatory cytokines associated with the onset of programmed cell death, suggesting this is a possible target in the development of chemotherapeutic agents for inducing cancer cell toxicity (8).…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A induces p53‑dependent endoplasmic reticulum stress in human colon cancer cells

Dai

Zhang

et al. 2018

Oncol Lett

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Trichostatin A (TSA) has been demonstrated to exhibit various anticancer effects that influence cell cycle arrest, cell proliferation and apoptosis of cancer cells. A potential association between TSA and endoplasmic reticulum (ER) function has been suggested but its anticancer mechanism involving the induction of ER stress is unknown. p53 has previously been demonstrated to regulate ER function in response to stress but its role involving TSA and ER stress in cancer cells is poorly understood. The current study identified that TSA induced ER stress in wild type (WT) HCT116 human colon cancer cells. Following TSA treatment, the ER stress markers GRP78 and GRP94 significantly increased without hyperacetylation of their promoter regions. The inositol-requiring enzyme 1 α (IRE1α)/X-box binding protein 1 (XBP1) pathway was implicated due to an association of phosphorylated IRE1α and spliced XBP1 with ER stress. However, luciferase reporter assay indicated that splicing events were attenuated in HCT116 TP53(-/-) cells. Furthermore, cell viability and apoptosis were revealed to depend on p53 during TSA treatment. Cell viability increased and the apoptosis rate decreased in HCT116 TP53(-/-) cells compared with WT HCT116 cells undergoing TSA treatment. In conclusion, the current study revealed that TSA may induce ER stress via a p53-dependent mechanism in colon cancer cells. This provides information that may assist the development of treatments that exploit the anticancer function of TSA.

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The pan‐deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines

Henrici

Montalbano

Neureiter

et al. 2013

Molecular Carcinogenesis

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Deacetylase inhibitors (DACi) are a new class of drugs with a broad spectrum of mechanisms that favor their application in cancer therapy. Currently, the exact mechanisms and cellular effects of DACi have not been fully elucidated. In addition to their effects on histone acetylation, DACi can interfere with gene expression via miRNA pathways. Treatment with panobinostat (LBH589), a novel potent DACi, led to the highly aberrant modulation of several miRNAs in hepatocellular carcinoma (HCC) cell lines as shown by miRNA array analysis. Among them, hsa-miR-19a, hsa-miR-19b1 and the corresponding precursors were down-regulated by panobinostat in TP53(-/-) Hep3B and TP53(+/+) HepG2 cell lines; hsa-miR30a-5p mature form only was suppressed in both HCC cell lines, as confirmed by further RT-qPCR analysis. In HCC cell lines, panobinostat caused the upregulation of the predicted miRNA targets APAF1 and Beclin1 protein levels. Transfection with oligonucleotides mimicking these miRNAs led to an increase in the viability rate of both cell lines as analyzed by impedance-based real-time cell analysis. In addition, transfecting miRNA mimicking oligonucleotides resulted in the decrease of APAF1, Beclin1 and PAK6 at the protein level, proving the regulating influence of the investigated miRNAs on gene final products. The overexpression of the above mentioned oncomiRs in Hep3B and HepG2 cell lines leads to cell proliferation and downregulation of cell death associated proteins. In our model, panobinostat exerts its anti-cancer effect by suppressing these miRNAs and restoring the expression of their corresponding tumor suppressor targets.

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Endoplasmic Reticulum Stress Plays a Pivotal Role in Cell Death Mediated by the Pan-Deacetylase Inhibitor Panobinostat in Human Hepatocellular Cancer Cells

Cited by 33 publications

References 59 publications

Autophagy-related cell death by pan-histone deacetylase inhibition in liver cancer

Autophagy-related cell death by pan-histone deacetylase inhibition in liver cancer

Trichostatin A induces p53‑dependent endoplasmic reticulum stress in human colon cancer cells

The pan‐deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines

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