The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation

VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis

Prospective analysis of circulating metabolites and endometrial cancer risk

Background: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. Results: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. Conclusion: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention

Serum metabolomic pertubations among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with multiple health effects. Mechanistic studies using metabolomics could provide supporting evidence for such associations by identifying relevant biological pathways. In this study, we investigated metabolic perturbations in a cohort of TCDD exposed workers to better understand TCDD related health effects. Eighty one workers who had been exposed to TCDD in the past and 63 nonexposed workers were included in the study. Serum metabolites were detected using ultra high pressure liquid chromatography coupled online to a Q-TOF Premier mass spectrometer with a scan range of 70-1,000 m/z. Current plasma levels of TCDD were determined by high-resolution gas chromatography/isotope dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure were estimated using a one-compartment first order kinetic model. Differentially expressed metabolites were identified using linear regression models, partial least squares regression (PLSr) and a regression-based Bayesian variable selection approach. Features that were present in all quality control samples and had a coefficient of variation 0.05). PLSr analyses and Bayesian variable selection regression analyses revealed no obvious metabolic perturbations associated with TCDD levels. This is the first metabolomic analysis related to TCDD exposure in humans. No significant metabolic features were identified. It is concluded that TCDD exposure at levels present in this study does not lead to significant perturbations of the serum metabolome. Environ. Mol. Mutagen. 54:558-565, 2013. © 2013 Wiley Periodicals, Inc

Serum metabolomic pertubations among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with multiple health effects. Mechanistic studies using metabolomics could provide supporting evidence for such associations by identifying relevant biological pathways. In this study, we investigated metabolic perturbations in a cohort of TCDD exposed workers to better understand TCDD related health effects. Eighty one workers who had been exposed to TCDD in the past and 63 nonexposed workers were included in the study. Serum metabolites were detected using ultra high pressure liquid chromatography coupled online to a Q-TOF Premier mass spectrometer with a scan range of 70-1,000 m/z. Current plasma levels of TCDD were determined by high-resolution gas chromatography/isotope dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure were estimated using a one-compartment first order kinetic model. Differentially expressed metabolites were identified using linear regression models, partial least squares regression (PLSr) and a regression-based Bayesian variable selection approach. Features that were present in all quality control samples and had a coefficient of variation 0.05). PLSr analyses and Bayesian variable selection regression analyses revealed no obvious metabolic perturbations associated with TCDD levels. This is the first metabolomic analysis related to TCDD exposure in humans. No significant metabolic features were identified. It is concluded that TCDD exposure at levels present in this study does not lead to significant perturbations of the serum metabolome. Environ. Mol. Mutagen. 54:558-565, 2013. © 2013 Wiley Periodicals, Inc

Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs

Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programs for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization