Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death.
Fatty acid synthase (FASN) is the terminal enzyme responsible for fatty acid synthesis and is up-regulated in tumors of various origins to facilitate their growth and progression. Because of several reports linking the FASN and proteasome pathways, we asked whether FASN inhibitors could combine with bortezomib, the Food and Drug Administration-approved proteasome inhibitor, to amplify cell death. Indeed, bortezomib treatment augmented suboptimal FASN inhibitor concentrations to reduce clonogenic survival, which was paralleled by an increase in apoptotic markers. Interestingly, FASN inhibitors induced accumulation of ubiquinated proteins and enhanced the effects of bortezomib treatment. In turn, bortezomib increased fatty acid synthesis, suggesting crosstalk between the pathways. We hypothesized that cell death resulting from crosstalk perturbation was mediated by increased unfolded protein response (UPR) signaling. Indeed, disruption of crosstalk activated and saturated the adaptation arm of UPR signaling, including eIF2alpha phosphorylation, activating transcription factor 4 expression, and X-box-binding protein 1 splicing. Furthermore, although single agents did not activate the alarm phase of the UPR, crosstalk interruption resulted in activated c-Jun NH2-terminal kinase and C/EBP homologous protein-dependent cell death. Combined, the data support the concept that the UPR balance between adaptive to stress signaling can be exploited to mediate increased cell death and suggests novel applications of FASN inhibitors for clinical use.
Little
Joy L
JL
Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.
Wheeler
Frances B
FB
Koumenis
Constantinos
C
Kridel
Steven J
SJ
D000943:Antigens, Differentiation / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011489:Protein Denaturation; D054645:Protein Phosphatase 1; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D046988:Proteasome Endopeptidase Complex