Intertwining of Cellular Osmotic Stress Handling Mechanisms and Heavy Metal Accumulation.

Osmoregulation mechanisms are engaged in the detoxification and accumulation of heavy metals in plants, microalgae and other microorganisms. The present review paper analyzes osmotic resistance organisms and their heavy metal accumulation mechanisms closely related to osmoregulation. In prokaryotic and eukaryotic microorganisms, such as the green algae-like protist Euglena, osmotic and heavy metal stresses share similar cell responses and mechanisms.

Energy Metabolism Behavior and Response to Microenvironmental Factors of the Experimental Cancer Cell Models Differ From That of Actual Human Tumors.

Analysis of the biochemical differences in the energy metabolism among bi-dimensional (2D) and tri-dimensional (3D) cultured cancer cell models and actual human tumors was undertaken. In 2D cancer cells, the oxidative phosphorylation (OxPhos) fluxes range is 2.5-19 nmol O2/min/mg cellular protein.

Synergistic celecoxib and dimethyl-celecoxib combinations block cervix cancer growth through multiple mechanisms.

Objective: The synergistic inhibitory effect of celecoxib (CXB) and dimethyl-celecoxib (DMC) plus paclitaxel (PA) or cisplatin (CP) on human cervix HeLa and SiHa cells was assessed at multiple cellular levels in order to elucidate the biochemical mechanisms triggered by the synergistic drug combinations.

Methods: The effect of CXB (5 μM)/CP (2 μM) or CXB (5 μM)/PA (15 μM) and DMC (15 μM)/CP (5 μM) or DMC (15 μM)/PA (20 μM) for 24 h was assayed on cancer cell proliferation, energy metabolism, mitophagy, ROS production, glycoprotein-P activity, DNA stability and apoptosis/necrosis.

Results: Drug combinations synergistically decreased HeLa and SiHa cell proliferation (>75%) and arrested cellular cycle by decreasing S and G2/M phases as well as the Ki67 content (HeLa) by 7.

Repurposing auranofin and meclofenamic acid as energy-metabolism inhibitors and anti-cancer drugs.

Objective: Cytotoxicity of the antirheumatic drug auranofin (Aur) and the non-steroidal anti-inflammatory drug meclofenamic acid (MA) on several cancer cell lines and isolated mitochondria was examined to assess whether these drugs behave as oxidative phosphorylation inhibitors.

Methods: The effect of Aur or MA for 24 h was assayed on metastatic cancer and non-cancer cell proliferation, energy metabolism, mitophagy and metastasis; as well as on oxygen consumption rates of cancer and non-cancer mitochondria.

Results: Aur doses in the low micromolar range were required to decrease proliferation of metastatic HeLa and MDA-MB-231 cells, whereas one or two orders of magnitude higher levels were required to affect proliferation of non-cancer cells.

Mitochondrial Proteins as Metabolic Biomarkers and Sites for Therapeutic Intervention in Primary and Metastatic Cancers.

Accelerated aerobic glycolysis is one of the main metabolic alterations in cancer, associated with malignancy and tumor growth. Although glycolysis is one of the most studied properties of tumor cells, recent studies demonstrate that oxidative phosphorylation (OxPhos) is the main ATP provider for the growth and development of cancer. In this last regard, the levels of mRNA and protein of OxPhos enzymes and transporters (including glutaminolysis, acetate and ketone bodies catabolism, free fatty acid β-oxidation, Krebs Cycle, respiratory chain, phosphorylating system- ATP synthase, ATP/ADP translocator, Pi carrier) are altered in tumors and cancer cells in comparison to healthy tissues and organs, and non-cancer cells.

Changes in landscape and climate in Mexico and Texas reveal small effects on migratory habitat of monarch butterflies (Danaus plexippus).

The decline of the iconic monarch butterfly (Danaus plexippus) in North America has motivated research on the impacts of land use and land cover (LULC) change and climate variability on monarch habitat and population dynamics. We investigated spring and fall trends in LULC, milkweed and nectar resources over a 20-year period, and ~ 30 years of climate variables in Mexico and Texas, U.S.

Colorectal polyps increase the glycolytic activity.

In colorectal cancer (CRC) energy metabolism research, the precancerous stage of polyp has remained rather unexplored. By now, it has been shown that CRC has not fully obtained the glycolytic phenotype proposed by O. Warburg and rather depends on mitochondrial respiration.

Lactate oxidation is linked to energy conservation and to oxygen detoxification via a putative terminal cytochrome oxidase in Methanosarcina acetivorans.

The marine archaeon Methanosarcina acetivorans contains a putative NAD  -independent d-lactate dehydrogenase (D-iLDH/glycolate oxidase) encoded by the MA4631 gene, belonging to the FAD-oxidase C superfamily. Nucleotide sequences similar to MA4631 gene, were identified in other methanogens and Firmicutes with >90 and 35-40% identity, respectively. Therefore, the lactate metabolism in M.

Estimation of energy pathway fluxes in cancer cells - Beyond the Warburg effect.

Glycolytic and respiratory fluxes were analyzed in cancer and non-cancer cells. The steady-state fluxes in energy metabolism were used to estimate the contributions of aerobic glycolytic and oxidative phosphorylation (OxPhos) pathways to the cellular ATP supply. The rate of lactate production - corrected for the fraction generated by glutaminolysis - is proposed as the appropriate way to estimate glycolytic flux.

17-β Estradiol up-regulates energy metabolic pathways, cellular proliferation and tumor invasiveness in ER+ breast cancer spheroids.

Several biological processes related to cancer malignancy are regulated by 17-β estradiol (E2) in ER+-breast cancer. To establish the role of E2 on the atypical cancer energy metabolism, a systematic study analyzing transcription factors, proteins, and fluxes associated with energy metabolism was undertaken in multicellular tumor spheroids (MCTS) from human ER+ MCF-7 breast cancer cells. At E2 physiological concentrations (10 and 100 nM for 24 h), both ERα and ERβ receptors, and their protein target pS2, increased by 0.

Protein acetylation effects on enzyme activity and metabolic pathway fluxes.

Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues also occurs in non-nuclear proteins. Hence, it has been suggested that this covalent modification is a mechanism that might regulate diverse metabolic pathways by modulating enzyme activity, stability, and/or subcellular localization or interaction with other proteins.

Celecoxib and Dimethylcelecoxib Block Oxidative Phosphorylation, Epithelial-Mesenchymal Transition and Invasiveness in Breast Cancer Stem Cells.

Background: The major hurdles for successful cancer treatment are drug resistance and invasiveness developed by breast cancer stem cells (BCSC).

Objective: As these two processes are highly energy-dependent, the identification of the main ATP supplier required for stem cell viability may result advantageous in the design of new therapeutic strategies to deter malignant carcinomas.

Methods: The energy metabolism (glycolysis and oxidative phosphorylation, OxPhos) was systematically analyzed by assessing relevant protein contents, enzyme activities, and pathway fluxes in BCSC.

Regulatory role of acetylation on enzyme activity and fluxes of energy metabolism pathways.

Background: Most of the enzymes involved in the central carbon metabolism are acetylated in Lys residues. It has been claimed that this covalent modification represents a novel regulatory mechanism by which both enzyme/transporter activities and pathway fluxes can be modulated.

Methods: To establish which enzymes are regulated by acetylation, a systematic experimental analysis of activities and acetylation profile for several energy metabolism enzymes and pathway fluxes was undertaken in cells and mitochondria.

Acetate Promotes a Differential Energy Metabolic Response in Human HCT 116 and COLO 205 Colon Cancer Cells Impacting Cancer Cell Growth and Invasiveness.

Under dysbiosis, a gut metabolic disorder, short-chain carboxylic acids (SCCAs) are secreted to the lumen, affecting colorectal cancer (CRC) development. Butyrate and propionate act as CRC growth inhibitors, but they might also serve as carbon source. In turn, the roles of acetate as metabolic fuel and protein acetylation promoter have not been clearly elucidated.

Non-Steroidal Anti-Inflammatory Drugs Increase Cisplatin, Paclitaxel, and Doxorubicin Efficacy against Human Cervix Cancer Cells.

This study shows that the non-steroidal anti-inflammatory drug (NSAID) celecoxib and its non-cyclooxygenase-2 (COX2) analogue dimethylcelecoxib (DMC) exert a potent inhibitory effect on the growth of human cervix HeLa multi-cellular tumor spheroids (MCTS) when added either at the beginning ("preventive protocol"; IC = 1 ± 0.3 nM for celecoxib and 10 ± 2 nM for DMC) or after spheroid formation ("curative protocol"; IC = 7.5 ± 2 µM for celecoxib and 32 ± 10 µM for DMC).

Kinetic modeling of glucose central metabolism in hepatocytes and hepatoma cells.

Background: Kinetic modeling and control analysis of a metabolic pathway may identify the steps with the highest control in tumor cells, and low control in normal cells, which can be proposed as the best therapeutic targets.

Methods: Enzyme kinetic characterization, pathway kinetic modeling and control analysis of the glucose central metabolism were carried out in rat (hepatoma AS-30D) and human (cervix HeLa) cancer cells and normal rat hepatocytes.

Results: The glycogen metabolism enzymes in AS-30D, HeLa cells and hepatocytes showed similar kinetic properties, except for higher AS-30D glycogen phosphorylase (GP) sensitivity to AMP.

Physiological Role of Glutamate Dehydrogenase in Cancer Cells.

increased growth rates and final densities of several human metastatic cancer cells. To assess whether glutamate dehydrogenase (GDH) in cancer cells may catalyze the reverse reaction of fixation, its covalent regulation and kinetic parameters were determined under near-physiological conditions. Increased total protein and phosphorylation were attained in -supplemented metastatic cells, but total cell GDH activity was unchanged.

Metabolic Control Analysis for Drug Target Prioritization in Trypanosomatids.

To validate therapeutic targets in metabolic pathways of trypanosomatids, the criterion of enzyme essentiality determined by gene knockout or knockdown is usually being applied. Since, it is often found that most of the enzymes/proteins analyzed are essential, additional criteria have to be implemented for drug target prioritization. Metabolic control analysis (MCA), often in conjunction with kinetic pathway modeling, offers such possibility for prioritization.

Marine Archaeon Enhances Polyphosphate Metabolism Under Persistent Cadmium Stress.

Phosphate metabolism was studied to determine whether polyphosphate (polyP) pools play a role in the enhanced resistance against Cd and metal-removal capacity of Cd-preadapted (CdPA) . Polyphosphate kinase (PPK), exopolyphosphatase (PPX) and phosphate transporter transcript levels and their activities increased in CdPA cells compared to control (Cnt) cells. K inhibited recombinant Ma-PPK and activated Ma-PPX, whereas divalent cations activated both enzymes.

Transcriptional Regulation of Energy Metabolism in Cancer Cells.

Cancer development, growth, and metastasis are highly regulated by several transcription regulators (TRs), namely transcription factors, oncogenes, tumor-suppressor genes, and protein kinases. Although TR roles in these events have been well characterized, their functions in regulating other important cancer cell processes, such as metabolism, have not been systematically examined. In this review, we describe, analyze, and strive to reconstruct the regulatory networks of several TRs acting in the energy metabolism pathways, glycolysis (and its main branching reactions), and oxidative phosphorylation of nonmetastatic and metastatic cancer cells.

Gamma-glutamylcysteine synthetase and tryparedoxin 1 exert high control on the antioxidant system in Trypanosoma cruzi contributing to drug resistance and infectivity.

Trypanothione (T(SH)) is the main antioxidant metabolite for peroxide reduction in Trypanosoma cruzi; therefore, its metabolism has attracted attention for therapeutic intervention against Chagas disease. To validate drug targets within the T(SH) metabolism, the strategies and methods of Metabolic Control Analysis and kinetic modeling of the metabolic pathway were used here, to identify the steps that mainly control the pathway fluxes and which could be appropriate sites for therapeutic intervention. For that purpose, gamma-glutamylcysteine synthetase (γECS), trypanothione synthetase (TryS), trypanothione reductase (TryR) and the tryparedoxin cytosolic isoform 1 (TXN1) were separately overexpressed to different levels in T.

FruBPase II and ADP-PFK1 are involved in the modulation of carbon flow in the metabolism of carbohydrates in Methanosarcina acetivorans.

To enhance our understanding of the control of archaeal carbon central metabolism, a detailed analysis of the regulation mechanisms of both fructose1,6-bisphosphatase (FruBPase) and ADP-phosphofructokinase-1 (ADP-PFK1) was carried out in the methanogen Methanosarcina acetivorans. No correlations were found among the transcript levels of the MA_1152 and MA_3563 (frubpase type II and pfk1) genes, the FruBPase and ADP-PFK1 activities, and their protein contents. The kinetics of the recombinant FruBPase II and ADP-PFK1 were hyperbolic and showed simple mixed-type inhibition by AMP and ATP, respectively.

Repurposing drugs as pro-oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers.

Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases.

Resveratrol inhibits cancer cell proliferation by impairing oxidative phosphorylation and inducing oxidative stress.

The resveratrol (RSV) efficacy to affect the proliferation of several cancer cell lines was initially examined. RSV showed higher potency to decrease growth of metastatic HeLa and MDA-MB-231 (IC = 200-250 μM) cells than of low metastatic MCF-7, SiHa and A549 (IC = 400-500 μM) and non-cancer HUVEC and 3T3 (IC≥600 μM) cells after 48 h exposure. In order to elucidate the biochemical mechanisms underlying RSV anti-cancer effects, the energy metabolic pathways and the oxidative stress metabolism were analyzed in HeLa cells as metastatic-type cell model.