Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

Arsura, Marcello; Panta, Ganesh R.; Bilyeu, Jennifer D.; Cavin, Lakita G.; Sovak, Mika A.; Oliver, Aundrea A; Factor, Valentina M.; Heuchel, Rainer; Mercurio, Frank; Thorgeirsson, Snorri S.; Sonenshein, Gail E.

doi:10.1038/sj.onc.1206132

Cited by 138 publications

(125 citation statements)

References 71 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Functional interactions between TGF␤ and NF-B in tumor cells have been addressed in previous publications, which, however, provide a confusing view, with TGF␤ playing the role of either an inhibitor or activator of NF-B-mediated signaling in different cell types (24)(25)(26). Assayed in stably transfected human 293 cells, we demonstrate that the activation of NF-B by TGF␤2 is rapid (Fig.…”

Section: Discussionmentioning

confidence: 84%

Secreted transforming growth factor β2 activates NF-κB, blocks apoptosis, and is essential for the survival of some tumor cells

Lü

Burdelya

Swiatkowski

et al. 2004

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

View full text Add to dashboard Cite

The basis of constitutive activation of NF-B, essential for survival and resistance to apoptosis in many tumors, is not well understood. We find that transforming growth factor ␤2 (TGF␤2), predominantly in its latent form, is secreted by several different types of tumor cell lines that exhibit constitutively active NF-B and that TGF␤2 potently stimulates the activation of NF-B in reporter cells. Suppression of TGF␤2 expression by small interfering RNA kills prostate cancer PC3 cells, indicating that the TGF␤2-NF-B pathway is important for their viability. These findings identify TGF␤2 as a potential target for therapeutic strategies to inhibit the growth of tumor cells that depend on constitutively active NF-B, or to sensitize them to treatment with cytotoxic drugs.prostate cancer ͉ small interfering RNA ͉ ELISA ͉ Smad

show abstract

Section: Discussionmentioning

confidence: 84%

Secreted transforming growth factor β2 activates NF-κB, blocks apoptosis, and is essential for the survival of some tumor cells

Lü

Burdelya

Swiatkowski

et al. 2004

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

View full text Add to dashboard Cite

show abstract

“…19 This activation of NF-kB has been implicated in liver tumor formation. 20 However, several members of the IAP (inhibitors of apoptosis) family, such as XIAP, NAIP and ML-IAP, activate JNK1 survival pathway through interaction with MAP3K7 and its activator TAB1. 21 Whether MAP3K7 can be pro-apoptotic or promote survival in the same cell, depending on conditions, or whether the two opposite functions are tissue specific is unknown.…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts

et al. 2009

View full text Add to dashboard Cite

A panel of kinases whose inhibition increased apoptosis of pancreatic adenocarcinoma cells in vitro was recently established. The aim of this work was to observe in a mouse xenograft model whether inhibition of these kinases would alter pancreatic tumor growth. Rate of apoptosis, caspase-3 activity and cell viability were assessed in two pancreatic cancer cell lines, MiaPaCa2 and BxPC3, after inhibiting selected kinases by transfection of specific siRNAs. For in vivo experiments, MiaPaCa2 cells were injected into the pancreas of nude mice, where they formed tumors. Inhibition of kinases was obtained by repeated intraperitoneal (i.p.) injections of modified O-Methyl (OMe) siRNAs specific for the selected kinases. Tumor volumes were assessed after 21 days. Among selected kinases, PAK7, MAP3K7 and CK2a were those whose inhibition increased apoptosis the most in vitro. Simultaneous inhibition of two of them increased apoptosis up to five times. Moreover, inhibiting these kinases had little effect on 10 non-pancreatic cell lines, suggesting pancreatic specificity. In vivo, OMe-siRNAs induced significant but incomplete inhibition of kinase expression (45-75%). Nevertheless, such inhibition resulted in a twofold increase in caspase-3 activity in tumors and a strong reduction in tumor volume (about 75%). In vivo inhibition by OMe-siRNAs of three survival kinases apparently specific for pancreatic cancer cells, PAK7, MAP3K7 and CK2a, decreases significantly the growth of xenografted MiaPaCa2 cells. This strategy is therefore of potential clinical interest.

show abstract

“…The importance of NF-B in the induction of COX-2 has been demonstrated in many reports (41-44, 62, 63). Furthermore, NF-B plays an important role in liver carcinogenesis (64,65). Activation of NF-B was observed frequently in hepatocarcinoma, and the essential role of NF-B for cancer growth was confirmed in several human cancer cell lines (66,67).…”

Section: Fig 3 Activation Of Nf-b During Er Stressmentioning

confidence: 90%

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Hung

Lei³

et al. 2004

Journal of Biological Chemistry

240

215

View full text Add to dashboard Cite

Expression of mutant proteins or viral infection mayinterfere with proper protein folding activity in the endoplasmic reticulum (ER). Several pathways that maintain cellular homeostasis were activated in response to these ER disturbances. Here we investigated which of these ER stress-activated pathways induce COX-2 and potentially oncogenesis. Tunicamycin and brefeldin A, two ER stress inducers, increased the expression of COX-2 in ML-1 or MCF-7 cells. Nuclear translocation of NF-B and activation of pp38 MAPK were observed during ER stress. I B␣ kinase inhibitor Bay 11-7082 or I B␣ kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2␣ phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-B DNA binding activity and COX-2 induction. Expression of mutant hepatitis B virus (HBV) large surface proteins, inducers of ER stress, enhanced the expression of COX-2 in ML-1 and HuH-7 cells. Transgenic mice showed higher expression of COX-2 protein in liver and kidney tissue expressing mutant HBV large surface protein in vivo. Similarly, increased expression of COX-2 mRNA was observed in human hepatocellular carcinoma tissue expressing mutant HBV large surface proteins. In ML-1 cells expressing mutant HBV large surface protein, anchorage-independent growth was enhanced, and the enhancement was abolished by the addition of specific COX-2 inhibitors. Thus, ER stress due either to expression of viral surface proteins or drugs can stimulate the expression of COX-2 through the NF-B and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

show abstract

Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

Cited by 138 publications

References 71 publications

Secreted transforming growth factor β2 activates NF-κB, blocks apoptosis, and is essential for the survival of some tumor cells

Secreted transforming growth factor β2 activates NF-κB, blocks apoptosis, and is essential for the survival of some tumor cells

Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Contact Info

Product

Resources

About