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The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-[kappa]B transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-[kappa]B has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-[kappa]B affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-[kappa]B-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-[kappa]B drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC., Introduction Tumor cells must adapt to the low nutrient concentrations in the tumor microenvironment (TME) in order to survive, proliferate, and spread to distant sites (1-4). The availability of nutrients, [...]

Constitutively active MYC and reactivated telomerase often coexist in cancers. While reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with cofactors, confers several growth advantages to cancer cells. It is known that the reactivation of TERT, the catalytic subunit of telomerase, is limiting for reconstituting telomerase activity in tumors. However, while reactivation of TERT has been functionally linked to the acquisition of several 'hallmarks of cancer' in tumors, the molecular mechanisms by which this occurs and whether these mechanisms are distinct from the role of telomerase on telomeres is not clear. Here, we demonstrated that first-generation TERT-null mice, unlike Tercnull mice, show delayed onset of MYC-induced lymphomagenesis. We further determined that TERT is a regulator of MYC stability in cancer. TERT stabilized MYC levels on chromatin, contributing to either activation or repression of its target genes. TERT regulated MYC ubiquitination and proteasomal degradation, and this effect of TERT was independent of its reverse transcriptase activity and role in telomere elongation. Based on these data, we conclude that reactivation of TERT, a direct transcriptional MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis., Introduction Telomerase, a ribonucleoprotein enzyme complex consisting of an RNA component (Terc) and the reverse transcriptase catalytic subunit (TERT), adds telomere repeats (TTAGGG) onto chromosome ends, compensating for the erosion [...]

In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in response to inflammatory, microbial, and toxic challenges. Sustained activation of JNK triggers programmed cell death (PCD), and hepatocyte survival during these challenges requires induction of the NF-[kappa]B pathway, which antagonizes this activation by upregulating target genes. Thus, modulation of JNK activity is crucial to the liver response to TNFR-mediated challenge. The basis for this modulation, however, is unknown. Here, we investigated the role of the NF-[kappa]B target Gadd45b in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b-/- mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in livers of Gadd45b-/- mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b-/- mice. Interestingly, Gadd45[beta] ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45[beta] as a potential therapeutic target in liver diseases., Introduction TNF-[alpha] is a pleiotropic cytokine that plays important roles in immunity, inflammation, and tumorigenesis (1), (2). Exposure to TNF-[alpha] induces either cell proliferation or programmed cell death (PCD) through [...]

Asbestos is the main cause of human malignant mesothelioma (MM). In vivo, macrophages phagocytize asbestos and, in response, release TNF-[alpha] and other cytokines that contribute to carcinogenesis through unknown mechanisms. In vitro, asbestos does not induce transformation of primary human mesothelial cells (HM); instead, asbestos is very cytotoxic to HM, causing extensive cell death. This finding raised an apparent paradox: How can asbestos cause MM if HM exposed to asbestos die? We found that asbestos induced the secretion of TNF-[alpha] and the expression of TNF-[alpha] receptor I in HM. Treatment of HM with TNF-[alpha] significantly reduced asbestos cytotoxicity. Through numerous technical approaches, including chemical inhibitors and small interfering RNA strategies, we demonstrate that, in HM, TNF-[alpha] activates NF-[kappa]B and that NF-[kappa]B activation leads to HM survival and resistance to the cytotoxic effects of asbestos. Our data show a critical role for TNF-[alpha] and NF-[kappa]B signaling in mediating HM responses to asbestos. TNF-[alpha] signaling through NF-[kappa]B-dependent mechanisms increases the percent of HM that survives asbestos exposure, thus increasing the pool of asbestos-damaged HM that are susceptible to malignant transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases in HM exposed to asbestos and an increased mitotic rate with fewer irregular metaphases in HM exposed to both TNF-[alpha] and asbestos. Our findings provide a mechanistic rationale for the paradoxical inability of asbestos to transform HM in vitro, elucidate and underscore the role of TNF-[alpha] in asbestos pathogenesis in humans, and identify potential molecular targets for anti-MM prevention and therapy. cancer | inflammation | mesothelioma

Author(s): Enrico De Smaele; Francesca Zazzeroni; Salvatore Papa; Dung U. Nguyen; Rongguan Jin; Joy Jones; Rong Cong; Guido Franzoso (corresponding author) In addition to coordinating immune and inflammatory responses, NF-κB/Rel [...]

IκB-α inhibits transcription factor NF-κB by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate IκB-α. This liberates NF-κB to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-κB correlates with phosphorylation of IκB-α and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 Of IκB-α was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-κB could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-κB., Proteolytic degradation of IκB-α is essential for activation of NF-κB [1-4]. When degradation is blocked by certain protease inhibitors that target proteasomes, activation of NF-κB is prevented. Physiologic stimulation also [...]

Human T-cell leukemia virus type I Tax protein posttranslationally activates NF-kappa-B in T cells by targeting cytoplasmic complexes containing the heterodimers p50 and p65 and the precursor protein p100. Tax utilizes its physical association with p100 to antagonize the cytoplasmic sequestration function of p100. NF-kappa-B dimers complex with p100 through the precursor protein's ankyrin domain. Tax mediates the nuclear translocation of NF-kappa-B dimers that are released from the multimeric complexes.

The regulation of transcription factor NF-kappa-B and its inhibitor, I-kappa-B-alpha was elucidated. Following stimulation by PMA or TNF-alpha, I-kappa-B-alpha was transiently removed with a concomitant translocation of NF-kappa-B from the cytoplasm to the nucleus. However, I-kappa-B-alpha transcripts could be quickly induced, leading to the restoration of the unstimulated state.

The role of the oncoprotein Bcl-3, an l-kappa-B-related protein with ankyrin repeat motifs, in the development of B cell chronic lymphocytic leukemias was investigated. The results showed that Bcl-3 tightly associates with p50B homodimers, which are prototypical transcription factors that bind to kappa-B sites. The Bcl-3-p50B complex is tethered to DNA via the p50B homodimer, thus allowing Bcl-3 to transactivate directly. These results suggest a novel role for Bcl-3 distinct from that of l-kappa-B. The implications for tumorigenesis are discussed.

The oncoprotein Bcl-3 assists kappa-B site-dependent genetic transcription in vivo by negating the inhibition of NF-kappa-B activity by p50/NF-kappa-B homodimers. Bcl-3, which is linked to the oncogene bcl-3 that may cause some cases of B-cell chronic lymphocytic leukemia, probably helps to stimulate the selection of NF-kappa-B-regulated genes including the genes controlling the human immunodeficiency virus.