Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

Alberti, Chiara; Pinciroli, Patrizia; Valeri, Barbara; Ferri, Renata; Ditto, Antonino; Umezawa, Kazuo; Sensi, Marialuisa; Canevari, Silvana; Tomassetti, Antonella

doi:10.1038/onc.2011.572

Cited by 107 publications

(104 citation statements)

References 35 publications

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“…signaling in the treatment of autoimmunity and cancer (21). Because EGFR activation can mediate both IL-6 production (24,25) and STAT3 activation, we investigated the role of EGFR in regulating STAT3 activation in response to IL-6.…”

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confidence: 99%

STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

Wang

Boxel-Dezaire

Cheon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

245

211

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The activation of STAT3 by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. Abnormal constitutive activation of STAT3, which contributes to the pathology of cancer and to chronic inflammatory diseases such as rheumatoid arthritis, occurs when negative regulation is not fully effective. SOCS3, the major negative regulator of STAT3, is induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 h after initial exposure of cells to members of the IL-6 family of cytokines by binding cooperatively to the common receptor subunit gp130 and JAKs 1 and 2. We show here that when the epidermal growth factor receptor (EGFR) is present and active, STAT3 is rephosphorylated about 4 h after exposure of cells to IL-6 or oncostatin M and remains active for many hours. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated.A fter ligand-induced dimerization of the IL-6 receptor (IL-6R), the associated kinases JAK1 and JAK2 cross-phosphorylate tyrosine residues of adjacent glycoprotein 130 (gp130) subunits of the complex. The SH2 domain of STAT3 binds to newly phosphorylated tyrosines, followed by the phosphorylation of Y705 of STAT3 (1). Two phosphorylated STAT3 monomers then dimerize and translocate to the nucleus,

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mentioning

confidence: 99%

STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

Wang

Boxel-Dezaire

Cheon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

245

211

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“…Many studies reported that NF-kB is constitutively activated by ErbB family in breast, ovarian, prostate, and colorectal cancers (42,43). We first demonstrated that NFkB activation through 2 pathways in HCC827 and PC9 Figure 7.…”

Section: Discussionmentioning

confidence: 99%

TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

Jing

Chen

et al. 2014

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2-[(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IkB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-kB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-kB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-kB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-kB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers. Mol Cancer Ther; 13(3); 617-29. Ó2014 AACR.

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“…Multiple studies displayed that NF-κB may play a vital role in transactivation of inflammatory factors, [34][35][36][37][38] we sought to further explore whether PKM2-dependent expression of CCL2 could be attributed to activation of NF-κB signaling pathway. In light of this, HT-29 and Caco-2 of CRC cells were treated with PKM2-shRNA and analyzed with western blotting for the activation of NF-κB.…”

Section: Pkm2 Interacts With P65 and Activates Nf-κb Signaling Pathwamentioning

confidence: 99%

Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment

Zou

Wang

et al. 2017

Tumour Biol.

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Development of colorectal cancer has been considered as a result of imbalance of pro-and anti-inflammatory intestinal microenvironment accompanied by macrophage recruitment. Despite macrophages are implicated in remodeling tumor microenvironment, the mechanism of macrophage recruitment is not fully elucidated yet. In this study, we reported clinical association of highly expressed pyruvate kinase M2 in colorectal cancer with macrophage attraction. The conditioned medium from Caco-2 and HT-29 cells with depleted pyruvate kinase M2 dramatically reduced macrophage recruitment, which is reversed by addition of, a critical chemotaxis factor to macrophage migration, rCCL2. Silencing of endogenous pyruvate kinase M2 markedly decreased CCL2 expression and secretion by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Endogenous pyruvate kinase M2 interacted with p65 and mediated nuclear factor-κB signaling pathway and mainly regulated phosphorylation of Ser276 on p65 nuclear factor-κB. In addition, inhibition of macrophage recruitment caused by pyruvate kinase M2 silencing was rescued by ectopic expression of p65. Interestingly, pyruvate kinase M2 highly expressed in colorectal cancer tissue, which is correction with macrophage distribution. Taken together, we revealed a novel mechanism of pyruvate kinase M2 in promoting colorectal cancer progression by recruitment of macrophages through p65 nuclear factor-κB-mediated expression of CCL2.

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Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

Cited by 107 publications

References 35 publications

STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment

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