Induction of endonuclease G-mediated apopotosis in human oral squamous cell carcinoma cells by protein kinase C inhibitor safingol

Hamada, Mareomi; Sumi, Toshiyuki; Iwai, Shigemitsu; Nakazawa, Mitsuhiro; Yura, Yoshiaki

doi:10.1007/s10495-005-3348-z

Cited by 31 publications

(34 citation statements)

References 35 publications

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“…The kidney is one of the primary organs of EndoG expression (Ruiz-Carrillo and Renaud, 1987;Prats et al, 1997). EndoG appears to be the most active endonuclease in cancer cells Hamada et al, 2006;Wang et al, 2008;Schneiders et al, 2009;Mercer et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Apoptotic Endonucleases by EndoG

Zhdanov

Fahmi

Wang

et al. 2015

DNA and Cell Biology

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Cells contain several apoptotic endonucleases, which appear to act simultaneously before and after cell death by destroying the host cell DNA. It is largely unknown how the endonucleases are being induced and whether they can regulate each other. This study was performed to determine whether apoptotic mitochondrial endonuclease G (EndoG) can regulate expression of other apoptotic endonucleases. The study showed that overexpression of mature EndoG in kidney tubular epithelial NRK-52E cells can increase expression of caspase-activated DNase (CAD) and four endonucleases that belong to DNase I group including DNase I, DNase X, DNase IL2, and DNase g, but not endonucleases of the DNase 2 group. The induction of DNase I-type endonucleases was associated with DNA degradation in promoter/exon 1 regions of the endonuclease genes. These results together with findings on colocalization of immunostained endonucleases and TUNEL suggest that DNA fragmentation after EndoG overexpression was caused by DNase I endonucleases and CAD in addition to EndoG itself. Overall, these data provide first evidence for the existence of the integral network of apoptotic endonucleases regulated by EndoG.

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Section: Introductionmentioning

confidence: 99%

Regulation of Apoptotic Endonucleases by EndoG

Zhdanov

Fahmi

Wang

et al. 2015

DNA and Cell Biology

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“…9 Cell death in the absence of caspase activation was, for example, reported from sulfasalazine-treated T cells, 10 placlitaxel treatment of ovarian carcinoma cells, 11 or safingolstimulated oral squamous cell carcinomas. 12 Death induction by these drugs is considered to involve the nuclear translocation of mitochondrial apoptogenic factors AIF or EndoG. Nuclear relocation of mitochondrial factors is often preceded by drug-mediated induction of reactive oxygen species (ROS) followed by mitochondrial relocalization of Bax and subsequent mitochondrial disintegration.…”

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confidence: 99%

4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG

et al. 2007

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Apoptosis is a major mechanism of treatment-induced T-cell depletion in leukemia and autoimmune diseases. While 'classical' apoptosis is considered to depend on caspase activation, caspase-independent death is increasingly recognized as an alternative pathway. Although the DNA-damaging drug cyclophosphamide (CY) is widely used for therapy of hematological malignancies and autoimmune disorders, the molecular mechanism of apoptosis induction remains largely unknown. Here, we report that treatment of Jurkat, cytotoxic, and primary leukemic T cells with an activated analog of CY, 4-hydroperoxycyclophosphamide (4-OOH-CY), induces caspase activation and typical features of apoptosis, although cell death was not prevented by caspase inhibition. Also depletion of murine thymocytes and splenocytes after CY treatment in vivo was not inhibited by Z-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD.fmk). Caspase-8 and receptor-induced protein (RIP) were dispensable for 4-OOH-CY-mediated apoptosis, while overexpression of Bcl-2 was partially protective. 4-OOH-CY treatment induced reactive oxygen species production, upregulation of Bax, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (EndoG). The antioxidant N-acetyl-L-cysteine substantially inhibited conformational changes of Bax, loss of mitochondrial membrane potential, nuclear relocation of mitochondrial factors, and apoptosis induction in 4-OOH-CYtreated T cells. These results strongly indicate that oxidative damage-induced nuclear translocation of AIF and EndoG in 4-OOH-CY-treated T cells might represent an alternative death pathway in the absence of caspase activity.

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“…However, substantial cell kill could be observed in our current study at this concentration of safingol, as demonstrated by MTT viability data and flow cytometry analyses. It is possible that exposure to high concentrations of safingol (40-50 μM) could lead to effective inhibition of PKC activity and phosphorylation of MARCKS (20,35), and that safingol could have inhibited PKC without interfering its phosphorylation site (20). Our results, on the other hand, are comparable with those reported by Hoffmann et al (17), whereby the IC 50 values of safingol in six cell lines of squamous cell carcinomas of head and neck ranged from 3.8-8.6 μM, similar to those obtained here.…”

Section: Discussionmentioning

confidence: 99%

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

Ling

Lin²,

Tan³

et al. 2009

Int J Oncol

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Abstract. Colon cancer represents one of the most common solid tumors in adults. Although 5-fluorouracil (5-FU) and irinotecan have been frequently administered in colon cancer patients, low response rates to these single drug therapies were reported. It is therefore imperative to search for new targeted combination therapies that are effective. In this study, we investigated the anti-cancer effect of safingol as a single agent or in combination with irinotecan using HT-29 and LS-174T colon cancer cells as our in vitro models. As a single agent, safingol was more potent than irinotecan and 5-FU, with IC 50 values of 2.5±1.1 μM and 3.4±1.0 μM achieved in HT-29 and LS-174T cells, respectively. However, protein kinase C (PKC) was not inhibited with concentrations of safingol which could induce substantial cell kill. The combination of safingol/irinotecan at 1:1 molar ratio was found to be additive in HT-29 cells (CI=0.94) and synergistic in LS-174T cells (CI=0.68), and resulted in concentration-and time-dependent down-regulation of p-PKC and p-MARCKS. The drug effect of the safingol/irinotecan combination was further modulated in the presence of a PKC stimulator (phorbol 12-myristate 13-acetate) or a PKC inhibitor (staurosporine). Furthermore, the 1:1 safingol/irinotecan combination inhibited the adhesion of colon cancer cells to the extracellular matrix 4-h post-treatment. Taken together, modulation of the PKC pathway could be a possible molecular basis for the observed synergism of the safingol/irinotecan combination, and these results demonstrate the therapeutic potential of this drug combination in colon cancer treatment.

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Induction of endonuclease G-mediated apopotosis in human oral squamous cell carcinoma cells by protein kinase C inhibitor safingol

Cited by 31 publications

References 35 publications

Regulation of Apoptotic Endonucleases by EndoG

Regulation of Apoptotic Endonucleases by EndoG

4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG

The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells

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