Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Rodríguez-Hernández, Ángeles; Navarro-Villarán, Elena; González, Raúl; Pereira, Sheila M.; Castro, Lysandra; Sarrias-Giménez, A.; Barrera-Pulido, L.; Álamo-Martínez, J.M.; Serrablo-Requejo, Alejandro; Blanco‐Fernández, Gerardo; Nogales-Muñoz, Á.; Gila-Bohórquez, A.; Pacheco, Dimitri E.; Torres-Nieto, M.A.; Serrano-Díaz-Canedo, J.; Suárez-Artacho, G.; Bellido, C. Bernal; Marín-Gómez, L.M.; Bárcena, José Antonio; Gómez‐Bravo, Miguel Ángel; Padilla, C. Alicia; Padillo, Francisco J.; Muntané, Jordi

doi:10.1016/j.redox.2015.07.010

Cited by 20 publications

(10 citation statements)

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“…Specifically, apoptosis elicited by the multi-kinase inhibitor sorafenib is associated with a decrease in nitrosylation of TNFR1. The data support a model in which the downregulation of receptor nitrosylation by sorafenib may shift the balance from survival to apoptosis [86].…”

Section: Death Receptorssupporting

confidence: 77%

“…How nitrosylation modulates receptor activity is not known, but it was speculated that it may cause a conformational change and render the receptor more sensitive to activation by its ligand [85]. Distinct from these findings, a recent study indicates that decreased nitrosylation promotes TNF-mediated apoptosis in hepatoblastoma cells [86]. Specifically, apoptosis elicited by the multi-kinase inhibitor sorafenib is associated with a decrease in nitrosylation of TNFR1.…”

Section: Death Receptorsmentioning

confidence: 99%

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Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Benhar

2020

Antioxidants

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It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, nitrosative stress and dysregulated cell death are implicated in a wide variety of pathological conditions, including cancer, cardiovascular and neurological diseases. Therefore, much effort is devoted to elucidate the molecular mechanisms linking oxidant/antioxidant systems and cell death pathways. This review is focused on thiol redox modifications as a major mechanism by which oxidants and antioxidants influence specific regulated cell death pathways in mammalian cells. Growing evidence indicates that redox modifications of cysteine residues in proteins are involved in the regulation of multiple cell death modalities, including apoptosis, necroptosis and pyroptosis. In addition, recent research suggests that thiol redox switches play a role in the crosstalk between apoptotic and necrotic forms of regulated cell death. Thus, thiol-based redox circuits provide an additional layer of control that determines when and how cells die.

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Section: Death Receptorssupporting

confidence: 77%

Section: Death Receptorsmentioning

confidence: 99%

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Benhar

2020

Antioxidants

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“…18) Sorafenib is a drug that induces the nitrosylation of cell-death receptors and modulates the production of nitric oxide. 19,20) Therefore, the inhibition of nitrosylation by VC may contribute to the protection of STAT3 phosphorylation, but further experiments are necessary to demonstrate our hypothesis.…”

Section: Discussionmentioning

confidence: 82%

Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

Yamamoto

Shichiri

Ishida³

et al. 2017

Biological & Pharmaceutical Bulletin

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Hand-foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenibinduced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.Key words vitamin C; multi-targeted tyrosine kinase inhibitor; hand-foot skin reaction (HFSR); ascorbic acidThe treatment for metastasis renal cell carcinoma has led to significant advances by molecular targeted drugs. However, some safety issues have recently emerged. In particular, adverse reactions induced by multiple tyrosine kinase inhibitors (mTKIs) are some of the major causes for the interruption of therapy involving these drugs. 1) Dermatological adverse events, also called hand−foot skin reaction, manifest topically in the palmar and plantar regions, and the pathological mechanism underlying these events is unclear. Because there are few treatment options for renal cell carcinoma and hepatocellular carcinoma, the success of therapy is determined by the length of efficient treatment and the management of adverse reactions. Therefore, appropriate management of the side effects will lead to an improvement in not only the QOL, but also the outcome of therapy 2,3) Although the dermatological adverse reactions induced by mTKIs are recognized as serious problems in clinical practice, a preventive method based on the pathological mechanism of these drugs has not been established.Previously, we reported that the inhibition of signal transducer and activator of transcription 3 (STAT3) contributes to the mechanism for keratinocyte toxicity induced by mTKIs, 4) and that the development of hand-foot skin reaction induced by mTKIs is associated with STAT3 polymorphisms. 5)STAT3 is a well-known transcriptional factor that regulates ce...

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“…The expression of p53 isoforms and cell death receptors were analyzed in HCC tissue by immunohistochemistry, and by Western-Blot analysis in cell lysate [14] or in cytoplasmic/nuclear [15] fractions. Deparaffinized tissue sections (5 μm) were hydrated, blocked specific sites, and incubated with primary antibodies against TNF-R1 (sc-7895, Santa Cruz Biotechnology, Santa Cruz, CA, USA), CD95 (sc-715), TRAIL-R1 (sc-6823), TAp63 (sc-8608) (TAp63α, TAp63β and TAp63γ), ΔNp63 (sc-71827) (ΔNp63α), TAp73 (Img-246, Imgenex, San Diego, CA, USA) (TAp73α, TAp73β and TAp73γ), and ΔNp73 (Img-313 A) (ΔNp73) overnight at room temperature in wet chamber.…”

Section: Methodsmentioning

confidence: 99%

Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation

González

Rosa

Rufini³

et al. 2017

PLoS ONE

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Background & AimsPatients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines.MethodsHCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells.ResultsThe reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation.ConclusionsThe reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.

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Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Cited by 20 publications

References 57 publications

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation

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