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Effect of Dietary ω-3 Polyunsaturated Fatty Acid DHA on Glycolytic Enzymes and Warburg Phenotypes in Cancer.

Manzi L, Costantini L, Molinari R, Merendino N - Biomed Res Int (2015)

Bottom Line: The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are a class of lipids that has been shown to have beneficial effects on some chronic degenerative diseases such as cardiovascular diseases, rheumatoid arthritis, inflammatory disorders, diabetes, and cancer.Recently, some in vitro studies showed that DHA promotes the inhibition of glycolytic enzymes and the Warburg phenotype.For example, it was shown that in breast cancer cell lines the modulation of bioenergetic functions is due to the capacity of DHA to activate the AMPK signalling and negatively regulate the HIF-1α functions.

View Article: PubMed Central - PubMed

Affiliation: Tuscia University, Department of Ecological and Biological Sciences, (DEB), Largo dell'Università, 01100 Viterbo, Italy.

ABSTRACT
The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are a class of lipids that has been shown to have beneficial effects on some chronic degenerative diseases such as cardiovascular diseases, rheumatoid arthritis, inflammatory disorders, diabetes, and cancer. Among ω-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) has received particular attention for its antiproliferative, proapoptotic, antiangiogenetic, anti-invasion, and antimetastatic properties, even though the involved molecular mechanisms are not well understood. Recently, some in vitro studies showed that DHA promotes the inhibition of glycolytic enzymes and the Warburg phenotype. For example, it was shown that in breast cancer cell lines the modulation of bioenergetic functions is due to the capacity of DHA to activate the AMPK signalling and negatively regulate the HIF-1α functions. Taking into account these considerations, this review is focused on current knowledge concerning the role of DHA in interfering with cancer cell metabolism; this could be considered a further mechanism by which DHA inhibits cancer cell survival and progression.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of the mechanism by which DHA may interfere with the molecular signalling by activating glycolytic phenotype. The PI3K-Akt-mTORC1 pathway promotes the glycolytic phenotype, principally activating the transcription factor HIF-1α. HIF-1α is activated also by hypoxia, as well as by mutations of its regulator VHL. The accumulation of HIF-1α in the cytosol determines its heterodimerization with the subunit HIF-1β, forming the active HIF-1 complex. HIF-1 upregulates a wide network of genes by binding to hypoxia response elements (HRE). DHA interferes at various sites of this pathway, and then it is able to attenuate bioenergetic function and Warburg metabolism. DHA treatment increases the LKB1 protein expression and AMP cytosolic levels, necessary events to activate the AMPK pathway. Active AMPK inhibits mTORC1 signalling, via phosphorylation of TSC protein. Moreover, DHA alters cancer cell metabolism by interfering with the processes implicated in the stabilization of HIF-1α. Indeed, the reduction of cytosolic ATP levels induced by DHA prevents the proper functioning of HSP90, molecular chaperon necessary for folding of HIF-1α. Moreover, DHA destabilizes HIF-1α promoting its proteolytic degradation via PPARα activation.
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig1: Schematic illustration of the mechanism by which DHA may interfere with the molecular signalling by activating glycolytic phenotype. The PI3K-Akt-mTORC1 pathway promotes the glycolytic phenotype, principally activating the transcription factor HIF-1α. HIF-1α is activated also by hypoxia, as well as by mutations of its regulator VHL. The accumulation of HIF-1α in the cytosol determines its heterodimerization with the subunit HIF-1β, forming the active HIF-1 complex. HIF-1 upregulates a wide network of genes by binding to hypoxia response elements (HRE). DHA interferes at various sites of this pathway, and then it is able to attenuate bioenergetic function and Warburg metabolism. DHA treatment increases the LKB1 protein expression and AMP cytosolic levels, necessary events to activate the AMPK pathway. Active AMPK inhibits mTORC1 signalling, via phosphorylation of TSC protein. Moreover, DHA alters cancer cell metabolism by interfering with the processes implicated in the stabilization of HIF-1α. Indeed, the reduction of cytosolic ATP levels induced by DHA prevents the proper functioning of HSP90, molecular chaperon necessary for folding of HIF-1α. Moreover, DHA destabilizes HIF-1α promoting its proteolytic degradation via PPARα activation.

Mentions: In a recent work, it was shown that DHA decreases the bioenergetic functions and metabolic reprogramming of breast cancer cell lines [20]. In this study, two metabolically distinct breast cancer cell lines were utilized, BT-474 and MDA-MB-231, representing mitochondrial and glycolytic phenotypes, respectively, and nontumorigenic breast epithelial cell line, MCF-10A, to identify the efficacy of DHA in multiple metabolic pathway. The extracellular acidification rate (ECAR), representative of glycolysis, and the oxygen consumption rate (OCR), representative of oxidative phosphorylation, were analysed in response to DHA treatment. Both parameters significantly decreased in the two cancer cell lines in a dose-dependent manner in response to DHA supplementation, compared with untreated cells but not in nontumorigenic control. These findings suggest that, independently of metabolic phenotype of cancer cells, DHA is able to change the bioenergetic profile. Moreover, DHA selectively targets malignant cell lines, since no effect was observed in the MCF-10A nontransformed cell line. The authors argue that the ability of DHA to interfere, not only with the glycolytic activity, but also with the mitochondrial respiration, is due to its capacity to alter the mitochondrial structure and function. Indeed, from the literature it is known that DHA may modify the mitochondrial phospholipid composition and alter the activity of essential inner membrane proteins and channels; this could lead to a reduction of mitochondrial bioenergetic function [52]. The reduction of oxidative phosphorylation is an effect that counteracts with the results obtained in the above discussed work of D'Alessandro et al., where the DHA-treated pancreatic cancer cell line showed a shift from glycolysis to Kreb's cycle [19]. It is possible that the DHA effects on mitochondrial functions are different among cell types. This may depend on the functional state of mitochondria themselves, as demonstrated in work of Suchorolski et al. [53]. In this work, it was compared with ECAR and OCR in four cell lines derived from Barrett's oesophagus (BE), a premalignant condition associated with an increased risk of oesophageal adenocarcinoma (EA), in response to metabolic inhibitors. The treatment with 2-deoxyglucose (2-DG), a competitive inhibitor of glycolytic pathway, increases the OCR value, only in the cell line CP-D. From the analysis of nuclear and mitochondria genome it was found that the CP-D line had the fewest number of mitochondrial genome mutations, among all cell lines. Since this cell line has functional mitochondria, it is able to revert the glycolytic metabolism towards oxidative phosphorylation [53]. Moreover, it is possible that the increased activity of Kreb's cycle, as a result of glycolysis inhibition, may be associated with the ability of some cells to oxidize alternative substrates like glutamine or fatty acids, which provide TCA cycle metabolites [54]. In the work of Mouradian et al., it was shown that the decrease of bioenergetic functions is associated with the reduction of HIF-1α expression and activity in DHA-treated breast cancer cell lines [20] (Figure 1). Further investigation found a reduction of downstream transcriptional targets of HIF-1α, glucose transporter 1 (GLUT1), and lactate dehydrogenase (LDH). The authors hypothesize that the DHA-induced decrease of HIF-1α can occur by two modalities: the first hypothesis expected that DHA induces degradation of HIF-1α protein through activation of PPARα. This consideration comes primarily from extensive scientific evidences that showed the ability of DHA and its metabolites to activate peroxisome proliferator-activated receptors (PPARs) [55, 56]. Moreover, in a recent work it has been demonstrated that the activation of PPARα by clofibrate suppressed HIF-1α signalling by increasing degradation of HIF-1α. The activated PPARα would seem to increase the interaction of HIF-1α with VHL, which enhances the ubiquitin-proteasome degradation pathway [57]. The other hypothesized mechanisms provide that the decrease of HIF-1α is due to a dysfunction of the HSP90 complex, which is required for a correct folding of this transcription factor [58]. Decreases of intracellular ATP levels attenuate the function of the HSP90 molecular chaperone; DHA treatment determines a reduction of ATP and so the disruption of the HSP90 function (Figure 1). The metabolic stress induced by DHA is demonstrated also by an increase in phospho-Thr172-AMPK in treated cells. This result is important evidence that DHA is able to modulate the AMPK pathway, which is implicated in reducing cell proliferation and in regulation of cell metabolism.


Effect of Dietary ω-3 Polyunsaturated Fatty Acid DHA on Glycolytic Enzymes and Warburg Phenotypes in Cancer.

Manzi L, Costantini L, Molinari R, Merendino N - Biomed Res Int (2015)

Schematic illustration of the mechanism by which DHA may interfere with the molecular signalling by activating glycolytic phenotype. The PI3K-Akt-mTORC1 pathway promotes the glycolytic phenotype, principally activating the transcription factor HIF-1α. HIF-1α is activated also by hypoxia, as well as by mutations of its regulator VHL. The accumulation of HIF-1α in the cytosol determines its heterodimerization with the subunit HIF-1β, forming the active HIF-1 complex. HIF-1 upregulates a wide network of genes by binding to hypoxia response elements (HRE). DHA interferes at various sites of this pathway, and then it is able to attenuate bioenergetic function and Warburg metabolism. DHA treatment increases the LKB1 protein expression and AMP cytosolic levels, necessary events to activate the AMPK pathway. Active AMPK inhibits mTORC1 signalling, via phosphorylation of TSC protein. Moreover, DHA alters cancer cell metabolism by interfering with the processes implicated in the stabilization of HIF-1α. Indeed, the reduction of cytosolic ATP levels induced by DHA prevents the proper functioning of HSP90, molecular chaperon necessary for folding of HIF-1α. Moreover, DHA destabilizes HIF-1α promoting its proteolytic degradation via PPARα activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538308&req=5

fig1: Schematic illustration of the mechanism by which DHA may interfere with the molecular signalling by activating glycolytic phenotype. The PI3K-Akt-mTORC1 pathway promotes the glycolytic phenotype, principally activating the transcription factor HIF-1α. HIF-1α is activated also by hypoxia, as well as by mutations of its regulator VHL. The accumulation of HIF-1α in the cytosol determines its heterodimerization with the subunit HIF-1β, forming the active HIF-1 complex. HIF-1 upregulates a wide network of genes by binding to hypoxia response elements (HRE). DHA interferes at various sites of this pathway, and then it is able to attenuate bioenergetic function and Warburg metabolism. DHA treatment increases the LKB1 protein expression and AMP cytosolic levels, necessary events to activate the AMPK pathway. Active AMPK inhibits mTORC1 signalling, via phosphorylation of TSC protein. Moreover, DHA alters cancer cell metabolism by interfering with the processes implicated in the stabilization of HIF-1α. Indeed, the reduction of cytosolic ATP levels induced by DHA prevents the proper functioning of HSP90, molecular chaperon necessary for folding of HIF-1α. Moreover, DHA destabilizes HIF-1α promoting its proteolytic degradation via PPARα activation.
Mentions: In a recent work, it was shown that DHA decreases the bioenergetic functions and metabolic reprogramming of breast cancer cell lines [20]. In this study, two metabolically distinct breast cancer cell lines were utilized, BT-474 and MDA-MB-231, representing mitochondrial and glycolytic phenotypes, respectively, and nontumorigenic breast epithelial cell line, MCF-10A, to identify the efficacy of DHA in multiple metabolic pathway. The extracellular acidification rate (ECAR), representative of glycolysis, and the oxygen consumption rate (OCR), representative of oxidative phosphorylation, were analysed in response to DHA treatment. Both parameters significantly decreased in the two cancer cell lines in a dose-dependent manner in response to DHA supplementation, compared with untreated cells but not in nontumorigenic control. These findings suggest that, independently of metabolic phenotype of cancer cells, DHA is able to change the bioenergetic profile. Moreover, DHA selectively targets malignant cell lines, since no effect was observed in the MCF-10A nontransformed cell line. The authors argue that the ability of DHA to interfere, not only with the glycolytic activity, but also with the mitochondrial respiration, is due to its capacity to alter the mitochondrial structure and function. Indeed, from the literature it is known that DHA may modify the mitochondrial phospholipid composition and alter the activity of essential inner membrane proteins and channels; this could lead to a reduction of mitochondrial bioenergetic function [52]. The reduction of oxidative phosphorylation is an effect that counteracts with the results obtained in the above discussed work of D'Alessandro et al., where the DHA-treated pancreatic cancer cell line showed a shift from glycolysis to Kreb's cycle [19]. It is possible that the DHA effects on mitochondrial functions are different among cell types. This may depend on the functional state of mitochondria themselves, as demonstrated in work of Suchorolski et al. [53]. In this work, it was compared with ECAR and OCR in four cell lines derived from Barrett's oesophagus (BE), a premalignant condition associated with an increased risk of oesophageal adenocarcinoma (EA), in response to metabolic inhibitors. The treatment with 2-deoxyglucose (2-DG), a competitive inhibitor of glycolytic pathway, increases the OCR value, only in the cell line CP-D. From the analysis of nuclear and mitochondria genome it was found that the CP-D line had the fewest number of mitochondrial genome mutations, among all cell lines. Since this cell line has functional mitochondria, it is able to revert the glycolytic metabolism towards oxidative phosphorylation [53]. Moreover, it is possible that the increased activity of Kreb's cycle, as a result of glycolysis inhibition, may be associated with the ability of some cells to oxidize alternative substrates like glutamine or fatty acids, which provide TCA cycle metabolites [54]. In the work of Mouradian et al., it was shown that the decrease of bioenergetic functions is associated with the reduction of HIF-1α expression and activity in DHA-treated breast cancer cell lines [20] (Figure 1). Further investigation found a reduction of downstream transcriptional targets of HIF-1α, glucose transporter 1 (GLUT1), and lactate dehydrogenase (LDH). The authors hypothesize that the DHA-induced decrease of HIF-1α can occur by two modalities: the first hypothesis expected that DHA induces degradation of HIF-1α protein through activation of PPARα. This consideration comes primarily from extensive scientific evidences that showed the ability of DHA and its metabolites to activate peroxisome proliferator-activated receptors (PPARs) [55, 56]. Moreover, in a recent work it has been demonstrated that the activation of PPARα by clofibrate suppressed HIF-1α signalling by increasing degradation of HIF-1α. The activated PPARα would seem to increase the interaction of HIF-1α with VHL, which enhances the ubiquitin-proteasome degradation pathway [57]. The other hypothesized mechanisms provide that the decrease of HIF-1α is due to a dysfunction of the HSP90 complex, which is required for a correct folding of this transcription factor [58]. Decreases of intracellular ATP levels attenuate the function of the HSP90 molecular chaperone; DHA treatment determines a reduction of ATP and so the disruption of the HSP90 function (Figure 1). The metabolic stress induced by DHA is demonstrated also by an increase in phospho-Thr172-AMPK in treated cells. This result is important evidence that DHA is able to modulate the AMPK pathway, which is implicated in reducing cell proliferation and in regulation of cell metabolism.

Bottom Line: The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are a class of lipids that has been shown to have beneficial effects on some chronic degenerative diseases such as cardiovascular diseases, rheumatoid arthritis, inflammatory disorders, diabetes, and cancer.Recently, some in vitro studies showed that DHA promotes the inhibition of glycolytic enzymes and the Warburg phenotype.For example, it was shown that in breast cancer cell lines the modulation of bioenergetic functions is due to the capacity of DHA to activate the AMPK signalling and negatively regulate the HIF-1α functions.

View Article: PubMed Central - PubMed

Affiliation: Tuscia University, Department of Ecological and Biological Sciences, (DEB), Largo dell'Università, 01100 Viterbo, Italy.

ABSTRACT
The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are a class of lipids that has been shown to have beneficial effects on some chronic degenerative diseases such as cardiovascular diseases, rheumatoid arthritis, inflammatory disorders, diabetes, and cancer. Among ω-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) has received particular attention for its antiproliferative, proapoptotic, antiangiogenetic, anti-invasion, and antimetastatic properties, even though the involved molecular mechanisms are not well understood. Recently, some in vitro studies showed that DHA promotes the inhibition of glycolytic enzymes and the Warburg phenotype. For example, it was shown that in breast cancer cell lines the modulation of bioenergetic functions is due to the capacity of DHA to activate the AMPK signalling and negatively regulate the HIF-1α functions. Taking into account these considerations, this review is focused on current knowledge concerning the role of DHA in interfering with cancer cell metabolism; this could be considered a further mechanism by which DHA inhibits cancer cell survival and progression.

No MeSH data available.


Related in: MedlinePlus