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Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; antiapoptotic proteins from the Bcl-2 family) inhibit autophagy. Similarly, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) induce autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, UVRAG and Bif-1) are bona fide oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. Within the nucleus, p53 can act as an autophagy-inducing transcription factor. Within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The role of autophagy in oncogenesis and anticancer therapy is contradictory. Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Altogether, the current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.Cell Death and Differentiation (2009) 16, 87–93; doi:10.1038/cdd.2008.131; published online 19 September 2008 [ABSTRACT FROM AUTHOR]

The transcription factor nuclear factor-κB (NF-κB) plays a key role in the expression of several genes involved in the inflammatory process. In the present study we investigated in an acute model of inflammation, the carrageenin-induced hind paw edema, the anti-inflammatory effect of double stranded oligodeoxynucleotides (ODN) with consensus nuclear factor-κB (NF-κB) sequence as transcription factor decoys (TFD) to inhibit NF-κB binding to native DNA sites. Local administration of wild-type, but not mutant-ODN decoy, dose-dependently inhibited edema formation induced by carrageenin in rat paw. Molecular analysis performed on soft tissue obtained from inflamed paw demonstrated: (1) an inhibition of NF-κB DNA binding activity; (2) a decreased nuclear level of p50 and p65 NF-κB subunits; (3) an inhibition of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression, two inflammatory enzymes transcriptionally controlled by NF-κB. Furthermore, SN-50, a cell-permeable peptide capable of inhibiting the nuclear translocation of NF-κB complexes, exhibited a similar profile of activity of ODN decoy. Our results indicate for the first time that ODN decoy, acting as an in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent a novel strategy to modulate acute inflammation. [ABSTRACT FROM AUTHOR]

We studied the involvement of nuclear factor-κB (NF-κB) in the regulation of inducible nitric oxide synthase expression in carrageenin-induced rat pleurisy. Injection of 0.2 ml of 1% λ-carrageenin into the pleural cavity of male Wistar rats caused after 6 h: (a) exudate formation and leukocyte migration into the pleural cavity; (b) inducible NO synthase protein expression and accumulation of NO2 – plus NO3 – in pleural exudate; (c) increase in p50/p65 nuclear level as well as ΝF-κB/DNA binding activity. Treatment of rats with pyrrolidine dithiocarbamate (10, 30, and 100 mg/kg) and N-α- p-tosyl- l-lysine chloromethylketone (30 mg/kg), two inhibitors of NF-κB activation, given subcutaneously concomitantly with carrageenin, caused a significant inhibition of all the parameters assayed. These results suggest that in carrageenin-induced rat pleurisy the activation of ΝF-κB plays a key role in inducible NO synthase protein expression and in the development of inflammatory response. [ABSTRACT FROM AUTHOR]