Abstract
The efficacy of drugs used to treat cancer can be significantly attenuated by adaptive responses of neoplastic cells to drug-induced stress. To determine how cancer cells respond to inhibition of the enzyme fatty acid synthase (FAS), we focused on NF-κB-mediated pathways, which can be activated by various cellular stresses. Treating lung cancer cells with C93, a pharmacological inhibitor of FAS, results in changes indicative of a rapid initiation of NF-κB signaling, including translocation of RelA/p65 NF-κB to the nucleus, activation of a transfected NF-κB-luciferase reporter, and increased expression of NF-κB-dependent transcripts, IL-6, IL-8, and COX-2. Verifying that these responses to C93 are specifically related to inhibition of FAS, we confirmed that levels of these same transcripts increase in response to siRNA targeting FAS. Inhibiting this NF-κB response (either by transfecting a mutant IκBα or treating with bortezomib) resulted in increased cell killing by C93, indicating that the NF-κB response is protective in this setting. Because inhibiting FAS leads to accumulation of intermediate metabolites of fatty acid biosynthesis, we then questioned whether protein kinase C (PKC) is involved in this response to metabolic stress. Immunofluorescence microscopy revealed that C93 treatment results in cellular translocation of PKCα and PKCβ isoforms and increased PKCα-dependent phosphorylation of the IκBα subunit of NF-κB. Furthermore, inhibiting PKC activity with RO-31-8220 or PKCα isoform-specific siRNA attenuates C93-induced IκBα phosphorylation and NF-κB activation and also potentiates C93-induced cell killing. These results suggest a link between PKC and NF-κB in protecting cancer cells from metabolic stress induced by inhibiting FAS.
Highlights
Key role in maintaining the metabolic stability of cancer cells, the molecular consequences of inhibiting fatty acid synthase (FAS) are still not well understood
Activation of PKC in Response to C93 Mediates the Activation of NF-B—We explored the possibility that the activation of NF-B induced by inhibiting fatty acid synthase is mediated by protein kinase C (PKC), which can be activated by a variety of lipid mediators [25] and in turn is reportedly capable of phosphorylating and inactivating IB␣ [26, 27]
We note that inhibiting FAS with C93 leads to a rapid translocation of the p65/ RelA subunit of NF-B to the nucleus, an increase in NF-B reporter activity, and increased cellular transcription of prosurvival target genes that are downstream of NF-B signaling
Summary
Key role in maintaining the metabolic stability of cancer cells, the molecular consequences of inhibiting FAS are still not well understood. At least in some cellular settings, inhibition or loss of NF-B activity abrogates p53-induced apoptosis, indicating that NF-B can be functional in p53-mediated cell death. Activation of NF-B by cancer therapeutic agents appears to mediate cell death in other circumstances, including treatment with UV light [18], doxorubicin [19], and paclitaxel [20]. In light of the general importance of NF-B to cellular physiology and response to stress and the expectation that manipulations of lipid metabolic pathways could affect NF-B signaling, we investigated the effects of inhibiting FAS on NF-B and the role of NF-B signaling in the response of lung cancer cells to this inhibition
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