Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells

Rihan, Mohd; Nalla, Lakshmi Vineela; Dharavath, Anil; Patel, Sagarkumar; Shard, Amit; Khairnar, Amit

doi:10.1016/j.bmcl.2022.128539

Cited by 13 publications

(4 citation statements)

References 38 publications

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“…Despite the mentioned limitations and gaps, this work could, for the first time, uncover moonlighting of PKM2 to be affected by Sfn in LPS-stimulated macrophages and may also be relevant for other settings. Likewise, modulation of PKM2 has already been exploited by various small molecules to mediate potential health benefits (e.g., 58 – 62 ). Staying in the field of immunology, Sfn-mediated interference with mono/dimer formation of PKM2 should be examined during Th1 or Th17 differentiation of T-helper cells ( 63 – 65 ), especially as Sfn already showed promise for diseases with a strong Th17 component, such as psoriasis ( 66 ) or arthritis ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane diminishes moonlighting of pyruvate kinase M2 and interleukin 1β expression in M1 (LPS) macrophages

et al. 2022

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Murine macrophages activated by the Toll-like receptor 4 agonist lipopolysaccharide (LPS) polarize to the M1 type by inducing proinflammatory marker proteins and changing their energy metabolism to increased aerobic glycolysis and reduced respiration. We here show that the aliphatic isothiocyanate sulforaphane (Sfn) diminishes M1 marker expression (IL-1β, IL-6, TNF-α, iNOS, NO, and ROS) and leads to highly energetic cells characterized by both high glycolytic and high respiratory activity as assessed by extracellular flux analysis. Focusing on a potential connection between high glycolytic activity and low IL-1β expression in M1 (LPS/Sfn) macrophages, we reveal that Sfn impedes the moonlighting function of pyruvate kinase M2 (PKM2) in M1 macrophages. Sfn limits mono/dimerization and nuclear residence of PKM2 accompanied by reduced HIF-1α levels, Stat3 phosphorylation at tyrosine 705, and IL-1β expression while preserving high levels of cytosolic PKM2 tetramer with high glycolytic enzyme activity. Sfn prevents glutathionylation of PKM2 in LPS-stimulated macrophages which may account for the reduced loss of PKM2 tetramer. Overall, we uncover PKM2 as a novel affected hub within the anti-inflammatory activity profile of Sfn.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane diminishes moonlighting of pyruvate kinase M2 and interleukin 1β expression in M1 (LPS) macrophages

et al. 2022

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“…The downregulation of pyruvate kinase (PK) and phosphoglycerate kinase (PGK1), restrictive enzymes of the glycolysis pathway, would depress the production of intracellular ATP. 46 Inhibition of the glycolytic and pentose phosphate pathways can reduce the required substrate that is essential for the TCA cycle, thereby causing a disordered energy metabolism (Figure 6I). Protein disulfide isomerase (PDI) is a key enzyme in the endoplasmic reticulum (ER) and promotes the secretion, folding, and assembly of membrane proteins in the endoplasmic reticulum.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The central carbon metabolism process, including glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle (TCA cycle), is significantly negatively influenced. The downregulation of pyruvate kinase (PK) and phosphoglycerate kinase (PGK1), restrictive enzymes of the glycolysis pathway, would depress the production of intracellular ATP . Inhibition of the glycolytic and pentose phosphate pathways can reduce the required substrate that is essential for the TCA cycle, thereby causing a disordered energy metabolism (Figure I).…”

Section: Discussionmentioning

confidence: 99%

Microcystins-Loaded Aged Nanoplastics Provoke a Metabolic Shift in Human Liver Cells

Shen

Salam

et al. 2023

Environ. Sci. Technol.

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Studies concerning the toxicity of pollutant-loaded nanoplastics (NPs) toward humans are still in their infancy. Here, we evaluated the adsorption of microcystins (MCs) by pristine and aged polystyrene nanoplastics (PSNPs), prepared MCs-loaded aged PSNPS (1, 5, 10, 15, and 19 μg/mg), and systematically mapped the key molecular changes induced by aged and MCs-loaded PSNPs to human hepatoblastoma (HepG2) cells. According to the results, MC-LR adsorption is increased 2.64-fold by aging, and PSNP accumulation is detected in HepG2 cells. The cytotoxicity of the MC-LR-loaded aged PSNPs showed a positive relationship with the MC-LR amount, as the cell viability in the 19 μg/mg loading treatment (aPS-MC19) was 10.84% lower than aged PSNPs; meanwhile, more severe oxidative damage was observed. Primary approaches involved stressing the endoplasmic reticulum and reducing protein synthesis that the aged PSNPs posed for HepG2 cells, while the aggravated cytotoxicity in aPS-MC19 treatment was a combined result of the metabolic energy disorder, oxidative damage, endoplasmic reticulum stress, and downregulation of the MC-LR target protein. Our results confirm that the aged PSNPs could bring more MC-LR into the HepG2 cells, significantly interfere with biological processes, and provide new insight into deciphering the risk of NPs to humans.

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“…Particularly, the PKM2 activity of compound 83 (Figure 4) was tested in CAL-27 cells. It was found that compound 83 activated PKM2 with an AC50 of 25 nM [154].…”

Section: Miscellaneamentioning

confidence: 99%

Unmasking the Warburg Effect: Unleashing the Power of Enzyme Inhibitors for Cancer Therapy

Angulo-Elizari,

Gaviria-Soteras,

Zubiri

et al. 2023

DDC

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The Warburg effect (or aerobic glycolysis), which was first described in 1926 by Otto Heinrich Warburg, consists of the change in glucose metabolism in cancer cells. In normal cells, glucose metabolism finalizes in the mitochondria through oxidative phosphorylation (OXPHOS) in the presence of oxygen. However, the Warburg effect describes a change in the glucose metabolism in cancer cells, consuming excess glucose and converting it into lactate independently of the presence of oxygen. During this process, a wide variety of enzymes can modify their expression and activity to contribute to the mechanism of deregulated cancer metabolism. Therefore, the modulation of enzymes regulating aerobic glycolysis is a strategy for cancer treatment. Although numerous enzymes play a role in regulating aerobic glycolysis, hexokinase 2 (HK2), pyruvate dehydrogenase kinase (PDK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) are worth mentioning. Numerous modulators of these enzymes have been described in recent years. This review aims to present and group, according to their chemical structure, the most recent emerging molecules targeting the above-mentioned enzymes involved in the Warburg effect in view of the future development of cancer treatments.

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Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells

Cited by 13 publications

References 38 publications

Sulforaphane diminishes moonlighting of pyruvate kinase M2 and interleukin 1β expression in M1 (LPS) macrophages

Sulforaphane diminishes moonlighting of pyruvate kinase M2 and interleukin 1β expression in M1 (LPS) macrophages

Microcystins-Loaded Aged Nanoplastics Provoke a Metabolic Shift in Human Liver Cells

Unmasking the Warburg Effect: Unleashing the Power of Enzyme Inhibitors for Cancer Therapy

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