Maintenance of Constitutive IκB Kinase Activity by Glycogen Synthase Kinase-3α/β in Pancreatic Cancer

Wilson, Willie; Baldwin, Albert S.

doi:10.1158/0008-5472.can-08-1061

Cited by 105 publications

(124 citation statements)

References 27 publications

(41 reference statements)

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“…GSK-3 has since been implicated in the TNF␣-induced activation of NF-B in several other cell types, including hepatocytes, renal epithelial cells, and intestinal epithelial cells, in addition to mouse fibroblasts (17, 19 -21). Consistent with the role of GSK-3 in inhibiting apoptosis induced by TNF␣ and in stimulating cytokine activation of NF-B, inhibition of GSK-3 has also been reported to induce apoptosis and to inhibit NF-B in some human cancer cell lines, particularly pancreatic carcinomas, in which the NF-B pathway is constitutively active (18,22,23).…”

Section: Discussionmentioning

confidence: 55%

“…It is also noteworthy that inhibition of GSK-3 can lead to the accumulation of nuclear ␤-catenin, which directly interacts with p65 to inhibit its transcriptional activity (47,48). However, GSK-3 has also been reported to affect the stability of IB␣ in hepatocytes (21) and to be required for maintenance of constitutive IKK activity in some pancreatic cancer cell lines (23).…”

Section: Discussionmentioning

confidence: 99%

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GSK-3 Represses Growth Factor-inducible Genes by Inhibiting NF-κB in Quiescent Cells

Graham

Tullai

Cooper

2010

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

GSK-3 Represses Growth Factor-inducible Genes by Inhibiting NF-κB in Quiescent Cells

Graham

Tullai

Cooper

2010

Journal of Biological Chemistry

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“…The data presented so far establish a link between the NF-κB activity and the circadian clock but does not provide an insight into the nature of this association. We considered GSK3β kinase as a potential candidate to link the two systems because GSK3β is known to activate NF-κB (21,22) and, recently, it was reported that the phosphorylated (inactive) form of GSK3β exhibited a circadian rhythm in the mouse liver with the inactive GSK3β-P in phase with BMAL1 and antiphase with CRY1 (23). Hence, we wished to determine how the interfacing of the molecular clock with NF-κB through GSK3β would impact the cytokine-initiated apoptosis in p53-null cells with a functional or disrupted circadian clock.…”

Section: Role Of Gsk3β In Linking the Circadian Clock To The Proapoptmentioning

confidence: 99%

Regulation of apoptosis by the circadian clock through NF-κB signaling

Lee

Sancar

2011

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

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In mice and humans the circadian rhythm of many biochemical reactions, physiology, and behavior is generated by a transcriptionaltranslation feedback loop (TTFL) made up of the so-called core clock genes/proteins. The circadian system interfaces with most signaling pathways including those involved in cell proliferation and inflammation. Cryptochrome (CRY) is a core clock protein that plays an essential role in the repressive arm of the TTFL. It was recently reported that mutation of CRY in p53-null mice delayed the onset of cancer. It was therefore suggested that CRY mutation may activate p53-independent apoptosis pathways, which eliminate premalignant and malignant cells and thus delay overt tumor formation. Here we show that CRY mutation sensitizes p53 mutant and oncogenically transformed cells to tumor necrosis factor α (TNFα)-initiated apoptosis by interfacing with the NF-κB signaling pathway through the GSK3β kinase and alleviating prosurvival NF-κB signaling. These findings provide a mechanistic foundation for the delayed onset of tumorigenesis in clock-disrupted p53 mutant mice and suggest unique therapeutic strategies for treating cancers associated with p53 mutation. hepatocellular carcinoma | inflammatory cytokine | extrinsic apoptotic pathway T he circadian rhythm in mammalian organisms is generated by a molecular clock comprising four gene/protein groups (1-5): The CLOCK (NPAS2) and BMAL1 transactivators and the cryptochrome 1 and 2 (CRY1/2) and the period 1 and 2 (PER1/ 2) repressors. CLOCK (or NPAS2) and BMAL1 make heterodimers, which act on the promoters of CRY1/2 and PER1/2 and activate their transcription. The CRY and PER proteins in turn, after a time delay of ill-defined mechanism, inhibit the CLOCK-BMAL1 transactivator and hence their own transcription to close the TTFL. This core TTFL directly or indirectly affects most cellular functions, and as a result, clock disruption by core clock gene mutation is expected to have serious repercussions at the cellular and organismal levels.We recently reported that mice of the p53 −/− Cry1 −/− Cry −/− (hereafter p53 KO Cry DKO ) genotype exhibited delayed onset of spontaneous cancer relative to p53 −/− (p53 KO ) mice (6). When analyzed for their response to genotoxic stress, it was found that p53 KO Cry DKO cells were more sensitive to UV-induced apoptosis than p53 KO cells even though they are identical in terms of DNA repair and DNA damage checkpoint functions (6). Therefore, we ascribed the reduced clonogenic survival of p53 KO Cry DKO cells upon UV irradiation, relative to p53 KO cells, to enhanced p53-independent apoptosis as a consequence of CRY mutation. We also suggested that the delayed onset of cancer and prolonged lifespan of mice of p53 KO Cry DKO genotype may have been caused by enhanced apoptosis of oncogenically transformed cells before giving rise to macroscopic tumors (6). In line with these findings we recently determined that p53 KO Cry DKO tumors are more responsive to oxaliplatin than p53 KO tumors (7). However, UV and oxaliplatin...

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“…GSK-3b is accumulated in the nucleus of renal cancer cells GSK-3b has been shown as positive regulator of NF-kB-mediated survival and proliferation of cancer cells (Ougolkov et al, , 2007Wilson and Baldwin, 2008). Recently, we have shown aberrant nuclear accumulation of GSK-3b in pancreatic cancer and leukaemia cells (Ougolkov et al, 2006(Ougolkov et al, , 2007.…”

Section: Gsk-3b Is Expressed and Active In Human Renal Cancer Cellsmentioning

confidence: 99%

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

et al. 2009

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BACKGROUND: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3b positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-kB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3b and to assess the anti-cancer effect of GSK-3b inhibition in RCC. METHODS: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3b in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT -PCR, BrDU incorporation and MTS assays to study the effect of GSK-3b inactivation on renal cancer cell proliferation and survival. RESULTS: We detected aberrant nuclear accumulation of GSK-3b in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF-kB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells. CONCLUSIONS: Our results show nuclear accumulation of GSK-3b as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.

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Maintenance of Constitutive IκB Kinase Activity by Glycogen Synthase Kinase-3α/β in Pancreatic Cancer

Cited by 105 publications

References 27 publications

GSK-3 Represses Growth Factor-inducible Genes by Inhibiting NF-κB in Quiescent Cells

GSK-3 Represses Growth Factor-inducible Genes by Inhibiting NF-κB in Quiescent Cells

Regulation of apoptosis by the circadian clock through NF-κB signaling

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

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