UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth

UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)–TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.

UDP-glucose pyrophosphorylase 2, a regulator of glycosylation and glycogen, is essential for pancreatic cancer growth

Pancreatic ductal adenocarcinomas (PDACs) have enhanced nutrient uptake requirements and rapid metabolic processing. The enzyme UDP-glucose pyrophosphorylase 2 (UGP2) rests at the convergence of multiple metabolic pathways, however the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an essential role for UGP2 in the maintenance of PDAC growth in both in vitro and in vivo tumor models. Transcription of UGP2 is directly regulated by the YAP/TEAD complex. Loss of UGP2 leads to decreased intracellular glycogen and defects in N-glycosylation targets important for cell growth including epidermal growth factor receptor (EGFR). In murine xenograft models, knockdown of UGP2 halted tumor growth and repressed expression of EGFR. The critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer new avenues of therapy for otherwise intractable PDACs.Impact StatementConvergent findings reveal that UDP-glucose pyrophosphorylase 2 has a central role in growth and metabolism of pancreatic ductal adenocarcinomas, highlighting novel therapeutic possibilities for this deadly cancer.

Assessment of the Sludge Reduction of the Metabolic Uncoupler 3,3′,4′,5-tetrachlorosalicylanilide (TCS) in Activated Sludge Culture

Batch experiments were completed to assess the sludge reduction of the metabolic uncoupler 3,3′,4′,5-tetrachlorosalicylanilide (TCS). The effects of various TCS concentrations on sludge yield were evaluated and the mechanisms associated with sludge reduction were assessed. We discovered that TCS addition resulted in a reduction in sludge. Furthermore, a low dose of TCS (≤3 mg/L) resulted in a slight reduction in the efficiency of the wastewater treatment system, while >3 mg/L TCS reduced matrix removal efficiency, with an especially remarkable inhibition effect on ammonia removal. An increase in TCS addition was associated with a gradual decrease in both the electron transport system (ETS) activity and the specific cellular ATP (SATP) in the TCS system. It was demonstrated that TCS plays an important role in metabolic uncoupling. However, with the addition of TCS, both contents and compositions were increased, and the protein content increased more than polysaccharide production in extracellular polymeric substances (EPS). At TCS concentrations of ≤3 mg/L, DNA content was stable, but it increased rapidly from 4.97 mg/L to 15.34 mg/L as the TCS concentration was elevated from 6 mg/L to 12 mg/L. This implied that the mechanisms of sludge reduction were different for different TCS concentrations, including uncoupling metabolism, maintenance metabolism and lysis–cryptic growth.

Kinetics of Vinyl Acetate Biodegradation by Pseudomonas fluorescens PCM 2123

The microbial degradation of vinyl acetate (VA) by Pseudomonas fluorescens PCM 2123 strain was studied in both batch and continuous modes. The purpose of the experiments was to determine the kinetic model of the cell growth and biodegradation rate of vinyl acetate (VA), which was the sole carbon and energy source for tested microorganisms. The experiments, carried out in a batch reactor for several initial concentrations of growth substrate in the liquid phase ranging from 18.6 to 373 gsubstrate·m−3 (gs·m−3) made it possible to choose the kinetic model and to estimate its constants. The Haldane inhibitory model with the values of constants: μm = 0.1202 h−1, KS = 17.195 gs·m−3, Ki = 166.88 gs·m−3 predicted the experimental data with the best accuracy. To set the parameters of maintenance metabolism it was necessary to carry out a series of continuous cultures at different dilution rates (0.05 to 0.072 h−1) and concentrations of VA in the liquid supplied to the chemostat ranging from 30.9 to 123.6 gs·m−3. The obtained data-base enabled to determine the coefficient for maintenance metabolism (me = 0.0251 gsubstrate gcell dry weight−1·h−1 (gs·gcdw−1·h−1)) as well as the maximal and observed values of yield coefficients, Yxs M = 0.463 gcdw·gs−1 and (Yxs)obs = 0.411 gcdw·gs−1, respectively. The developed kinetics was verified by comparison of the computed and obtained in batch experiments profiles of changes in biomass and growth substrate concentrations.

Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy!

Hormone-independent malignancy is a major issue of morbidity and deaths that confronts prostate cancer. Despite decades of research, the oncogenic and hormonal implications in the development and progression of prostate malignancy remain mostly speculative. This is largely due to the absence and/or lack of consideration by contemporary clinicians and biomedical investigators regarding the established implications of the co-regulation of testosterone and prolactin in the development, maintenance, metabolism and functions of the prostate gland. Especially relevant is the major metabolic function of production of high levels of citrate by the peripheral zone acinar epithelial cells. Citrate production, along with growth and proliferation by these cells, is regulated by co-existing testosterone and prolactin signaling pathways; and by the oncogenic down-regulation of ZIP1 transporter/zinc/citrate in the development of malignancy. These relationships had not been considered in the issues of hormonedependent malignancy. This review provides the relevant background that has established the dual role of testosterone and prolactin regulation of the prostate gland; which is essential to address the implications in the oncogenic development and progression of hormone-dependent malignancy. The oncogenic factor along with testosterone-dependent and prolactin-dependent relationships leads to the plausible concept that androgen ablation for the treatment of testosterone-dependent malignancy results in the development of prolactin-dependent malignancy; which is testosterone-independent malignancy. Consequently, both testosterone ablation and prolactin ablation are required to prevent and/or abort terminal hormonedependent prostate cancer.

A microcalorimetric approach for investigating stoichiometric constraints on the standard metabolic rate of a small invertebrate

Abstract1: Understanding the determinant of metabolism is a core ecological topic since it permits to link individuals energetic requirements to the ecology of communities and ecosystems. Yet, besides temperature, the effects of environmental factors on metabolism remain poorly understood. For example, dietary stoichiometric constraints have been hypothesized to increase maintenance metabolism of small invertebrates, yet experimental support remains scarce.2: Here, we used microcalorimetric heat flow measurements to determine the standard metabolic rate (SMR) of Daphnia magna throughout its ontogeny when fed stoichiometrically balanced (C/P ratio:166) or imbalanced (C/P ratio:1439) diets.3: When fed a stoichiometrically imbalanced diet, daphnids were able to maintain the stoichiometric homeostasis within narrow boundaries. However, they consistently increased their SMR while decreasing their somatic growth rate. Our measurements unequivocally demonstrate that homeostatic regulation implies higher metabolic costs and thereby reduces the portion of energy that can be allocated to growth.4: Our study demonstrates that microcalorimetry is a powerful and precise tool for measuring the metabolic rate of small-sized organisms and opens promising perspectives for understanding how environmental factors, such as nutritional constraints, affect organismal metabolism.