ArticleMolecular cancer2010
Selective unresponsiveness to the inhibition of p38 MAPK activation by cAMP helps L929 fibroblastoma cells escape TNF-alpha-induced cell death.
Article in Molecular cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 19 citations in OpenAlex.
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- RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog.Theranostics · 2019Article
- RACK1 antagonizes TNF-α-induced cell death by promoting p38 activation.Scientific reports · 2015Article
- The Gβγ-Src signaling pathway regulates TNF-induced necroptosis via control of necrosome translocation.Cell research · 2014Article
- RACK1 promotes the proliferation of THP1 acute myeloid leukemia cells.Molecular and cellular biochemistry · 2013Article
- Chronic psychological stress induces the accumulation of myeloid-derived suppressor cells in mice.PloS one · 2013Article
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5 authors at 1 institution.
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Abstract
backgroundThe cyclic AMP (cAMP) signaling pathway has been reported to either promote or suppress cell death, in a cell context-dependent manner. Our previous study has shown that the induction of dynein light chain (DLC) by cAMP response element-binding protein (CREB) is required for cAMP-mediated inhibition of mitogen-activated protein kinase (MAPK) p38 activation in fibroblasts, which leads to suppression of NF-kappaB activity and promotion of tumor necrosis factor-alpha (TNF-alpha)-induced cell death. However, it remains unknown whether this regulation is also applicable to fibroblastoma cells.
methodsIntracellular cAMP was determined in L929 fibroblastoma cells after treatment of the cells with various cAMP elevation agents. Effects of cAMP in the presence or absence of the RNA synthesis inhibitor actinomycin D or small interfering RNAs (siRNAs) against CREB on TNF-alpha-induced cell death in L929 cells were measured by propidium iodide (PI) staining and subsequent flow cytomety. The activation of p38 and c-Jun N-terminal protein kinase (JNK), another member of MAPK superfamily, was analyzed by immunoblotting. JNK selective inhibitor D-JNKi1 and p38 selective inhibitor SB203580 were included to examine the roles of JNK and p38 in this process. The expression of DLC or other mediators of cAMP was analyzed by immunoblotting. After ectopic expression of DLC with a transfection marker GFP, effects of cAMP on TNF-alpha-induced cell death in GFP+ cells were measured by PI staining and subsequent flow cytomety.
resultsElevation of cAMP suppressed TNF-alpha-induced necrotic cell death in L929 fibroblastoma cells via CREB-mediated transcription. The pro-survival role of cAMP was associated with selective unresponsiveness of L929 cells to the inhibition of p38 activation by cAMP, even though cAMP significantly inhibited the activation of JNK under the same conditions. Further exploration revealed that the induction of DLC, the major mediator of p38 inhibition by cAMP, was impaired in L929 cells. Enforced inhibition of p38 activation by using p38 specific inhibitor or ectopic expression of DLC reversed the protection of L929 cells by cAMP from TNF-alpha-induced cell death.
conclusionThese data suggest that the lack of a pro-apoptotic pathway in tumor cells leads to a net survival effect of cAMP.
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