Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1

Andrade-Vieira, Rafaela; Han, Jae Ho; Marignani, Paola A.

doi:10.4161/cbt.26206

Cited by 26 publications

(20 citation statements)

References 41 publications

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“…amino acids, nucleosides and lipids required for assembling new cells). This idea is supported by recent findings showing that dietary LC-O3PUFAs reduce glycolysis by decreasing the expression of glycolytic enzymes [48]. The reduced levels of selective amino acids with concomitant increases in the levels of urea and ornithine further support the strong influence of dietary PUFAs in modulating neural bioenergetics.…”

Section: Discussionsupporting

confidence: 61%

Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

Figueroa

León

2014

Mol Neurobiol

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Long-chain omega-3 polyunsaturated fatty acids (LC-O3PUFAs) exhibit therapeutic potential for the treatment and prevention of the neurological deficits associated with spinal cord injury (SCI). However, the mechanisms implicated in these protective responses remain unclear. The objective of the present functional metabolomics study was to identify and define the dominant metabolic pathways targeted by dietary LC-O3PUFAs. Sprague-Dawley rats were fed rodent purified chows containing menhaden fish oil-derived LC-O3PUFAs for 8 weeks before being subjected to sham or spinal cord contusion surgeries. We show, through untargeted metabolomics, that dietary LC-O3PUFAs regulate important biochemical signatures associated with amino acid metabolism and free radical scavenging in both the injured and sham-operated spinal cord. Of particular significance, the spinal cord metabolome of animals fed with LC-O3PUFAs exhibited reduced glucose levels (−48%) and polar uncharged/hydrophobic amino acids (<−20%) while showing significant increases in the levels of antioxidant/anti-inflammatory amino acids and peptides metabolites, including β-alanine (+24%), carnosine (+33%), homocarnosine (+27%), kynurenine (+88%), when compared to animals receiving control diets (p < 0.05). Further, we found that dietary LC-O3PUFAs impacted the levels of neurotransmitters and the mitochondrial metabolism, as evidenced by significant increases in the levels of N-acetylglutamate (+43%) and acetyl-CoA levels (+27%), respectively. Interestingly, this dietary intervention resulted in a global correction of the pro-oxidant metabolic profile that characterized the SCI-mediated sensorimotor dysfunction. In summary, the significant benefits of metabolic homeostasis and increased antioxidant defenses unlock important neurorestorative pathways of dietary LC-O3PUFAs against SCI.

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Section: Discussionsupporting

confidence: 61%

Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

Figueroa

León

2014

Mol Neurobiol

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“…If the nanoprobes do not activate EGF‐mediated pathways leading to cell growth and division and avoid an immune response, they would become excellent candidates for future biodistribution and pharmacokinetic studies in mouse cancer models, induced by subcutaneous injection of cancer cells; viral, chemical or hormonal agents; or genetic manipulation . We plan to focus on a mouse cancer model that appears to mimic human premalignant progression . The latter animal model is available through our collaborator (P. Marignani) at the same institution.…”

Section: Resultsmentioning

confidence: 99%

Development of a sensitive, stable and EGFR‐specific molecular imaging agent for surface enhanced Raman spectroscopy

Lucas

Tellez

Castilho

et al. 2015

J Raman Spectroscopy

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We created and studied a novel nanoprobe for spectroscopic molecular imaging of the epidermal growth factor (EGF) receptor, whose over-expression is a hallmark of a wide range of cancers. Silver nanoparticles (AgNPs) of 45 nm diameter were synthesized and coupled to EGF by α-lipoic acid, a short ligand that exhibits excellent silver binding affinity. Time-of-flight mass spectroscopy demonstrates formation of the protein complex. Enzyme-linked immunosorbent assay verifies the protein complex is 100% active for the EGF receptor, alone and, following conjugation to silver nanoparticles. Compared with its monosulfide analog, 6-mercaptohexanoic acid, α-lipoic acid is stabilized by binding to silver with a total energy that is lower by 1.38 eV, as found from Density Functional Theory (DFT)/natural bond analysis calculations. A Highest Occupied Molecular Orbital (HOMO)-Lowest Unoccupied Molecular Orbital (LUMO) gap energy of 5.25 (spin-up electrons) and 5.74 eV (spin-down electrons) was obtained for the silver-α-lipoic acid complex. This is the first report of silver nanoparticles being attached to EGF, and the first theoretical and experimental report on the surface enhanced Raman spectroscopy spectral interpretation of α-lipoic acid bound to silver. These nanoprobes exhibit surface enhanced Raman spectroscopy, when aggregated in solution, at picomolar concentrations and have the necessary propertiesspecificity, sensitivity and stabilityto serve as molecular imaging agents.

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“…Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using XF24 analyzer (Seahorse Bioscience) as previously described [ 50 ]. Primary LKB1 −/− NIC mammary tumor cells were isolated, then plated at 1×10 4 per well in Dulbecco modified Eagle's medium (DMEM).…”

Section: Methodsmentioning

confidence: 99%

Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

et al. 2014

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Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1−/−NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1−/−NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers.

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Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1

Cited by 26 publications

References 41 publications

Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

Development of a sensitive, stable and EGFR‐specific molecular imaging agent for surface enhanced Raman spectroscopy

Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

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