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- Title
Inflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation.
- Authors
Schmid, Tobias; Bajer, Magdalena M.; Blees, Johanna S.; Eifler, Lisa K.; Milke, Larissa; Rübsamen, Daniela; Schulz, Kathrin; Weigert, Andreas; Baker, Alyson R.; Colburn, Nancy H.; Brüne, Bernhard
- Abstract
The tumor suppressor programmed cell death 4 (Pdcd4) is lost in various tumor tissues. Loss of Pdcd4 has been associated with increased tumorigenic potential and tumor progression. While various mechanisms of Pdcd4 regulation have been described, the effect of an inflammatory tumor microenvironment on Pdcd4 protein expression has not been characterized so far. In the present study, we aimed to elucidate the molecular mechanisms of Pdcd4 protein regulation in tumor cells under inflammatory conditions. 12-O-tetradecanoylphorbol 13-acetate-induced differentiation of human U937 monocytes increased the expression and secretion of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-6 and IL-8. Exposure to conditioned medium (CM) of these activated macrophages markedly decreased Pdcd4 protein expression in various tumor cells. Similarly, indirect coculture with such activated U937 monocyte-derived macrophages resulted in the loss of Pdcd4 protein in tumor cells. Decreased Pdcd4 protein levels were attributable to enhanced proteasomal degradation, diminishing Pdcd4 protein half-life. Proteasomal degradation required activation of phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling. Since macrophage-CM sufficed to induce Pdcd4 degradation, Pdcd4 downregulation was determined to be an indirect unidirectional effect of the macrophages on the tumor cells. Pdcd4 protein expression was also attenuated in vivo in mouse colon tissue in response to dextran sodium sulfate-induced colitis. In summary, we characterized PI3K–mTOR-dependent proteasome-mediated Pdcd4 degradation in tumor cells in the inflammatory tumor microenvironment. Consequently, stabilization of Pdcd4 protein could provide a promising novel avenue for therapeutics targeting inflammation-associated tumors.
- Subjects
INFLAMMATION; PHOSPHORYLATION; TUMOR suppressor genes; CELL death; DISEASE progression; CYTOKINES; TUMOR necrosis factors
- Publication
Carcinogenesis, 2011, Vol 32, Issue 10, p1427
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgr131