Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death

Arlt, Alexander; Gehrz, André; Müerköster, Susanne Sebens; Vorndamm, Jens; Kruse, Marie‐Luise; Fölsch, Ulrich R.; Schäfer, Heiner

doi:10.1038/sj.onc.1206390

Cited by 464 publications

(391 citation statements)

References 33 publications

(37 reference statements)

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“…The present series of experiments does not establish that the sensitising effects of APE/ref-1 antisense is due to suppression of its BER activity, since APE/ref-1 also acts as a redox regulator of several transcription factors including NF-kB and AP1 that can promote cell survival responses (Hirota et al, 1997;Arrigo, 1999;Ueno et al, 1999;Moos et al, 2003). For example, the activation of NF-kB can occur during treatment with cancer chemotherapy and is believed to promote drug resistance (Wang et al, 1999;Baldwin, 2001;Arlt et al, 2003). The increases in APE/ref-1 seen in pancreas cancer cells during treatment with gemcitabine might augment this NF-kB response, additional to any effects on BER.…”

Section: Discussionmentioning

confidence: 66%

Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides

et al. 2004

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Apurinic/apyrimidinic endonuclease (APE) is a key enzyme involved in DNA base excision repair (BER) that is often expressed at elevated levels in human cancers. Pancreatic cancer cells treated with the nucleoside analogue gemcitabine (2 0 , 2 0 -difluoro-2 0 deoxycytidine) showed increases in APE/redox effector factor (ref-1) protein levels (approximately two-fold for Panc-1 and six-fold for MiaPaCa-2), with corresponding increases in endonuclease activity. These results suggested that the activation of APE/ref-1 might be an adaptive response that contributes to gemcitabine resistance by facilitating BER. To test this hypothesis, we examined the effects of disrupting APE/ref-1 using antisense on gemcitabine toxicity. Antisense oligonucleotides decreased protein levels three-fold in MiaPaCa-2 and five-fold in Panc-1 in comparison to controls, associated with reduced endonuclease activity. Combination treatments with antisense oligonucleotides and gemcitabine partially suppressed the increase in APE/ref-1 activity seen in cells exposed to gemcitabine alone. While clonogenic assays showed only slight decreases in colony formation in cells treated with either antisense oligonucleotides or gemcitabine alone, the combination with APE/ref-1 antisense resulted in a 2-log enhancement of gemcitabine toxicity in Panc-1 cells. Overall these findings suggest that APE/ref-1 plays a significant role in gemcitabine resistance in some pancreatic cancer cells, and support the further investigation of novel treatments that target this protein.

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Section: Discussionmentioning

confidence: 66%

Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides

et al. 2004

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“…In line with these data, we have shown that NF-kB inhibition may be a strategy to increase sensitivity to Etoposide-induced apoptosis in a cell line derived from a CML blast crisis. We have first shown that Etoposide, which is extensively used in the therapy of myeloid leukemias, activates NF-kB in K562 cell line, as it has been described in pancreatic cancer cell lines [21][22][23]. Interestingly, the kinetic of activation is sensibly different to that observed with the traditional NF-kB activator, TNF-a.…”

Section: Discussionmentioning

confidence: 89%

NF‐kB inhibition as a strategy to enhance etoposide‐induced apoptosis in K562 cell line

et al. 2006

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“…The observation that patients overexpressing RelA show a dramatically decreased survival time may allow stratifying patients into two subgroups: one subgroup is likely to benefit from NF-kB-inhibiting agents and another subgroup which has a relatively good survival perspective irrespective of such a treatment, potentially because resistance to conventional chemotherapeutics due to NF-kB activation has not occurred yet (Arlt et al, 2001(Arlt et al, , 2003. This possibility should be considered when clinical trials with NF-kB-inhibiting agents are being planned.…”

Section: Shuklamentioning

confidence: 99%

“…Furthermore, they profiled a small set of pancreatic tumours immunohistochemically and detected nuclear RelA. In another study, NF-kB was found to be activated in a number of pancreatic cancer cell lines, which was later linked to chemotherapy resistance (Arlt et al, 2001(Arlt et al, , 2003. Consequently, inhibition of NF-kB activation in these cell lines using sulfasalazine or the proteasome inhibitor MG-132 resulted in their sensitisation to etoposide, doxorubicin (Arlt et al, 2001) and gemcitabine (Arlt et al, 2003).…”

mentioning

confidence: 99%

“…In another study, NF-kB was found to be activated in a number of pancreatic cancer cell lines, which was later linked to chemotherapy resistance (Arlt et al, 2001(Arlt et al, , 2003. Consequently, inhibition of NF-kB activation in these cell lines using sulfasalazine or the proteasome inhibitor MG-132 resulted in their sensitisation to etoposide, doxorubicin (Arlt et al, 2001) and gemcitabine (Arlt et al, 2003). More recently, overexpression of several NF-kB subunits was described in the cytoplasm as well as in the nucleus of the pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3 (Chandler et al, 2004).…”

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confidence: 99%

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High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.

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Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death

Cited by 464 publications

References 33 publications

Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides

Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides

NF‐kB inhibition as a strategy to enhance etoposide‐induced apoptosis in K562 cell line

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

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