Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death

Kloster, Martine Müller; Naderi, Elin Hallan; Carlsen, Harald; Blomhoff, Heidi Kiil; Naderi, Soheil

doi:10.1186/1476-4598-10-45

Cited by 17 publications

(14 citation statements)

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“…More recently, it was shown that excessive DNA damage-induced NF-kB activation promoted expression of IL-6 in HELA cells (37). Upon chemotherapyinduced DDR, the I-kB kinase (IKK) complex phosphorylates Ik-Ba for ubiquination and proteasomal degradation, thus allowing the NF-kB complex to translocate to the nucleus (18,38). As the DDR pathway-activated NF-kB-mediated production of PGE 2 and IL-6 only occurred in tumor cell lines originally producing sufficient amounts of IL-6 and/or PGE 2 , an autocrine role for these cytokines can be envisaged ref.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment

et al. 2013

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Current therapy of gynecologic malignancies consists of platinum-containing chemotherapy. Resistance to therapy is associated with increased levels of interleukin (IL)-6 and prostaglandin E2 (PGE 2 ), 2 inflammatory mediators known to skew differentiation of monocytes to tumor-promoting M2 macrophages. We investigated the impact of cisplatin and carboplatin on 10 different cervical and ovarian cancer cell lines as well as on the ability of the tumor cells to affect the differentiation and function of cocultured monocytes in vitro. Treatment with cisplatin or carboplatin increased the potency of tumor cell lines to induce IL-10-producing M2 macrophages, which displayed increased levels of activated STAT3 due to tumor-produced IL-6 as well as decreased levels of activated STAT1 and STAT6 related to the PGE 2 production of tumor cells. Blockade of canonical NF-kB signaling showed that the effect of the chemotherapy was abrogated, preventing the subsequent increased production of PGE 2 and/or IL-6 by the tumor cell lines. Treatment with the COX-inhibitor indomethacin and/or the clinical monoclonal antibody against interleukin-6 receptor (IL-6R), tocilizumab, prevented M2-differentiation. Importantly, no correlation existed between the production of PGE 2 or IL-6 by cancer cells and their resistance to chemotherapy-induced cell death, indicating that other mechanisms underlie the reported chemoresistance of tumors producing these factors. Our data suggest that a chemotherapy-mediated increase in tumor-promoting M2 macrophages may form an indirect mechanism for chemoresistance. Hence, concomitant therapy with COX inhibitors and/or IL-6R antibodies might increase the clinical effect of platinum-based chemotherapy in otherwise resistant tumors. Cancer Res; 73(8); 2480-92. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment

et al. 2013

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“…However, cAMP also induced protein kinase C (PKC) activity in this study, which might explain the discrepant results. Activation of IKK by cAMP was recently also demonstrated in acute lymphoblastic leukemia cells [94]. The fact that the role of cAMP is often supported solely by the use of pharmacological cAMP/PKA activators/inhibitors, the selectivity of which is disputable, is indeed an important obstacle in the interpretation of many of the reported studies [95,96].…”

Section: Effects Of Camp On Ikk Activation and Cellular Ijb Levelsmentioning

confidence: 99%

Cyclic AMP: a selective modulator of NF-κB action

Gerlo

Kooijman

Beck

et al. 2011

Cell. Mol. Life Sci.

162

142

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It has been known for several decades that cyclic AMP (cAMP), a prototypical second messenger, transducing the action of a variety of G-protein-coupled receptor ligands, has potent immunosuppressive and anti-inflammatory actions. These actions have been attributed in part to the ability of cAMP-induced signals to interfere with the function of the proinflammatory transcription factor Nuclear Factor-kappaB (NF-κB). NF-κB plays a crucial role in switching on the gene expression of a plethora of inflammatory and immune mediators, and as such is one of the master regulators of the immune response and a key target for anti-inflammatory drug design. A number of fundamental molecular mechanisms, contributing to the overall inhibitory actions of cAMP on NF-κB function, are well established. Paradoxically, recent reports indicate that cAMP, via its main effector, the protein kinase A (PKA), also promotes NF-κB activity. Indeed, cAMP actions appear to be highly cell type- and context-dependent. Importantly, several novel players in the cAMP/NF-κB connection, which selectively direct cAMP action, have been recently identified. These findings not only open up exciting new research avenues but also reveal novel opportunities for the design of more selective, NF-κB-targeting, anti-inflammatory drugs.

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“…Controlled by activation of RAS at the cell surface interior, the subsequent stimulation of Raf and then MEK and ERK serves to regulate a range of key intracellular effectors associated with cell proliferation, 1 invasion, 2 angiogenesis, 3 and apoptotic resistance. 4 Mutated RAS is associated with almost one-third of human cancers, and a majority of malignant melanomas and papillary thyroid cancers harbor B-Raf mutations.…”

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confidence: 99%

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

Rice

Aay

Anand

et al. 2012

ACS Med. Chem. Lett.

141

108

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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials. KEYWORDS: MAPK pathway, MEK, cancer, kinase inhibitor, XL518, GDC-0973 T he MAPK cascade, or mitogen-activated protein kinase signal transduction pathway, is a mechanism commonly subject to dysregulation in cancer, and constitutive or highly upregulated signaling is a frequent hallmark of oncogenic transformation and progression. Controlled by activation of RAS at the cell surface interior, the subsequent stimulation of Raf and then MEK and ERK serves to regulate a range of key intracellular effectors associated with cell proliferation, 1 invasion, 2 angiogenesis, 3 and apoptotic resistance. 4 Mutated RAS is associated with almost one-third of human cancers, and a majority of malignant melanomas and papillary thyroid cancers harbor B-Raf mutations. 5,6 Inhibitors of MEK have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in preclinical models, and early development candidates including GSK1120212, In some tumors, activation of both the RAS driven ERK/ MAPK cascade and the PI3K-Akt pathway is observed, resulting in degenerate and convergent oncogenic signals, and upregulation or constitutive PI3K pathway activation is associated with resistance to MEK inhibitor single agent treatment.10 Several combination approaches using inhibitors of mTor, PI3K, Akt, and Raf have more recently been validated in preclinical models and are being pursued clinically. Herein, the discovery of XL518 (GDC-0973) (1), a potent and selective MEK inhibitor, is described. XL518 is currently in early stage clinical testing as both a single agent and in combination with the class I PI3K inhibitor GDC-0941. 11Our goal at the outset was the identification of a potent and selective MEK inhibitor with sustained duration of efficacy suitable for qd dosing and an optimized safety profile relative to clinical precursors. The diphenylamine series disclosed by the Pfizer/Warner Lambert groups served as a starting point for our effort. A key aspect tha...

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Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death

Cited by 17 publications

References 50 publications

Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment

Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment

Cyclic AMP: a selective modulator of NF-κB action

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

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