HDAC inhibitor-induced activation of NF-κB prevents apoptotic response of E1A+Ras-transformed cells to proapoptotic stimuli

Abramova, Maria V.; Zatulovskiy, Evgeny; Svetlikova, S. B.; Поспелов, В. А.

doi:10.1016/j.biocel.2010.08.001

Cited by 11 publications

(11 citation statements)

References 36 publications

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“…Moreover, NF-κB activation induced by HDACIs prevents apoptotic response of transformed cells to proapoptotic stimuli (Abramova et al, 2010). In this study, we found that TSA alone induced NF-κB activation in SGC7901 cells ( Fig.…”

Section: Discussionsupporting

confidence: 50%

ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism

Yao

Qian

et al. 2012

Life Sciences

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Section: Discussionsupporting

confidence: 50%

ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism

Yao

Qian

et al. 2012

Life Sciences

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“…The activation of AKT kinase signaling by HDACis has been observed in small cell lung cancer and rodent embryonic fibroblasts [39]–[41]; however, the mechanism underlying this effect has not been elucidated. Here we demonstrate that butyrate increases pAKT levels in CC cells in part through the noncanonical activity of WNT5A.…”

Section: Discussionmentioning

confidence: 99%

A Switch from Canonical to Noncanonical Wnt Signaling Mediates Drug Resistance in Colon Cancer Cells

et al. 2011

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Butyrate, a fermentation product of fiber in the colon, acts as a histone deacetylase inhibitor (HDACi) and induces apoptosis in colon cancer (CC) cells in vitro. We have reported that the apoptotic effects of butyrate are dependent upon the hyperactivation of the Wnt/beta-catenin pathway. However, prolonged exposure of CC cells to increasing concentrations of butyrate results in the acquisition of resistance to the Wnt/beta-catenin- and apoptosis-inducing effects of this agent, as well as cross-resistance to structurally different HDACis. Here we report that one mechanism whereby HDACi resistance arises is through the increase of beta-catenin-independent (noncanonical) Wnt signaling. Compared to HDACi-sensitive HCT-116 CC cells, HDACi-resistant HCT-R cells exhibit higher levels of AKT/PKB cell survival signaling, which is in part induced by WNT5A and its receptor ROR2. The induction of AKT signaling by HDACis is also detected in other CC cell lines, albeit to a lesser extent than in the drug-resistant HCT-R cells. The observations suggested that the apoptotic effect of butyrate and other HDACis in CC cells can be augmented by inhibitors of pAKT. In agreement with the hypothesis, the combination of MK2206, a pAKT inhibitor, and a HDACi (butyrate or LBH589) induced higher apoptosis in CC cells compared to each agent alone. The exposure to both agents also re-sensitized the HCT-R cells to apoptosis. Finally, the concept of simultaneously inducing canonical Wnt activity and suppressing AKT signaling was translated into a combination of diet-derived agents. Diet-derived pAKT inhibitors (caffeic acid phethyl ester, sulforaphane, dilallyl trisulfide) suppressed the butyrate-induced levels of pAKT, and increased the apoptotic effects of butyrate in both drug-sensitive and drug-resistant CC cells.Our findings can be translated into (a) CC therapy employing combinations of synthetic HDACis and inhibitors of pAKT, as well as (b) CC prevention based upon diets that result in sufficient amounts of butyrate and pAKT inhibitors.

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“…Thus, the effect of sodium butyrate on DNA damage response (IR) depends on the duration of HDACi treatment. As NaBut suppresses apoptosis in E1A+Ras cells due to activation of the NF-kB pathway, 23 the persistence of cH2AX foci is not a consequence of apoptosis-mediated DNA fragmentation. Instead, there is a correlation between accumulation of cH2AX foci and NaBut-induced senescence.…”

Section: Resultsmentioning

confidence: 94%

“…Accumulation of cH2AX foci was not due to apoptotic cell death because NaBut treatment was shown to suppress apoptosis in E1A+Ras cells. 23 To see which phase of the cell cycle is preferable for cH2AX foci induction, we treated E1A+Ras cells with NaBut for 2, 4 and 8 h (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…33 In our case, accumulation of cH2AX foci in cells treated with NaBut is not connected with apoptosis. 23 If ATM is not involved in phosphorylation of H2AX in NaBut-treated cells, what is the kinase phosphorylates H2AX? Recently we showed that rapamycin, an inhibitor of mTOR kinase activity, which was shown to suppress HDACi-and p21 overexpression-induced cellular senescence, also decreased NaBut-induced H2AX foci formation.…”

Section: Discussionmentioning

confidence: 99%

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HDAC inhibitor sodium butyrate sensitizes E1A+Ras-transformed cells to DNA damaging agents by facilitating formation and persistence of γH2AX foci

Abramova

Svetlikova

Кукушкин

et al. 2011

Cancer Biology & Therapy

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HDAC inhibitor-induced activation of NF-κB prevents apoptotic response of E1A+Ras-transformed cells to proapoptotic stimuli

Cited by 11 publications

References 36 publications

ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism

ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism

A Switch from Canonical to Noncanonical Wnt Signaling Mediates Drug Resistance in Colon Cancer Cells

HDAC inhibitor sodium butyrate sensitizes E1A+Ras-transformed cells to DNA damaging agents by facilitating formation and persistence of γH2AX foci

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