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Interplay Between HGF/SF-Met-Ras Signaling, Tumor Metabolism and Blood Flow as a Potential Target for Breast Cancer Therapy.

Natan S, Tsarfaty G, Horev J, Haklai R, Kloog Y, Tsarfaty I - Oncoscience (2013)

Bottom Line: In vitro, HGF/SF-activated Met increased Ras activity, Erk phosphorylation, cell motility and glucose uptake, but did not affect ATP.FTS inhibited basal and HGF/SF-induced signaling and cell motility, while further increasing glucose uptake and inhibiting ATP production.FTS did not affect basal blood-flow but abolished the HGF/SF effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University ; This work was done in partial fulfillment of the requirements for the Ph.D. degree of S.N.

ABSTRACT
High glucose uptake and increase blood flow is a characteristic of most metastatic tumors. Activation of Ras signaling increases glycolytic flux into lactate, de novo nucleic acid synthesis and uncoupling of ATP synthase from the proton gradient. Met tyrosine kinase receptor signaling upon activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF), increases glycolysis, oxidative phosporylation, oxygen consumption, and tumor blood volume. Ras is a key factor in Met signaling. Using the Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS), we investigated interplay between HGF/SF-Met-Ras signaling, metabolism, and tumor blood-flow regulation. In vitro, HGF/SF-activated Met increased Ras activity, Erk phosphorylation, cell motility and glucose uptake, but did not affect ATP. FTS inhibited basal and HGF/SF-induced signaling and cell motility, while further increasing glucose uptake and inhibiting ATP production. In vivo, HGF/SF rapidly increased tumor blood volume. FTS did not affect basal blood-flow but abolished the HGF/SF effect. Our results further demonstrate the complex interplay between growth-factor-receptor signaling and cellular and tumor metabolism, as reflected in blood flow. Inhibition of Ras signaling does not affect glucose consumption or basal tumor blood flow but dramatically decreases ATP synthesis and the HGF/SF induced increase in tumor blood volume. These findings demonstrate that the HGF/SF-Met-Ras pathway critically influences tumor-cell metabolism and tumor blood-flow regulation. This pathway could potentially be used to individualize tumor therapy based on functional molecular imaging, and for combined signaling/anti-metabolic targeted therapy.

No MeSH data available.


Related in: MedlinePlus

Inhibition of Ras in tumors affects Ras and pERK levels after a single dose of FTS(A), Activated Ras (Ras-GTP), pERK, and total Ras were assayed in xenografts prepared from DA3 tumors removed from mice at the indicated time periods after treatment with FTS (40 mg/kg) or vehicle (0.5% CMC). Western blot analysis demonstrates the rapid effect of FTS on ERK phosphorylation and on Ras activation and expression in vivo. (B), Bar graph depicting the average intensity (%) of each treatment relative to the control group. Black Bars represent Ras-GTP, white Bars represent pERK, and gray Bars represent total Ras. The results showed that FTS inhibits Ras-GTP, pERK, and total Ras as early as 4 hours after treatment.
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Figure 4: Inhibition of Ras in tumors affects Ras and pERK levels after a single dose of FTS(A), Activated Ras (Ras-GTP), pERK, and total Ras were assayed in xenografts prepared from DA3 tumors removed from mice at the indicated time periods after treatment with FTS (40 mg/kg) or vehicle (0.5% CMC). Western blot analysis demonstrates the rapid effect of FTS on ERK phosphorylation and on Ras activation and expression in vivo. (B), Bar graph depicting the average intensity (%) of each treatment relative to the control group. Black Bars represent Ras-GTP, white Bars represent pERK, and gray Bars represent total Ras. The results showed that FTS inhibits Ras-GTP, pERK, and total Ras as early as 4 hours after treatment.

Mentions: The effect of FTS on Ras signaling was measured at the specified time points in tumors from mice treated with 40 mg/kg FTS. Western blot analysis (Fig. 4A) shows the effects of FTS on Ras-GTP, pERK, and total Ras in the tumors of mice sacrificed 4 hours (lanes 5 to 7), 8 hours (lanes 8 to 11), or 24 hours (lanes 12 to15) after FTS treatment compared to those of control mice treated with the vehicle alone (lanes 1 to 4). These results showed that Ras signaling in tumors mammary is inhibited from as early as 4 hours after treatment with FTS.


Interplay Between HGF/SF-Met-Ras Signaling, Tumor Metabolism and Blood Flow as a Potential Target for Breast Cancer Therapy.

Natan S, Tsarfaty G, Horev J, Haklai R, Kloog Y, Tsarfaty I - Oncoscience (2013)

Inhibition of Ras in tumors affects Ras and pERK levels after a single dose of FTS(A), Activated Ras (Ras-GTP), pERK, and total Ras were assayed in xenografts prepared from DA3 tumors removed from mice at the indicated time periods after treatment with FTS (40 mg/kg) or vehicle (0.5% CMC). Western blot analysis demonstrates the rapid effect of FTS on ERK phosphorylation and on Ras activation and expression in vivo. (B), Bar graph depicting the average intensity (%) of each treatment relative to the control group. Black Bars represent Ras-GTP, white Bars represent pERK, and gray Bars represent total Ras. The results showed that FTS inhibits Ras-GTP, pERK, and total Ras as early as 4 hours after treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295761&req=5

Figure 4: Inhibition of Ras in tumors affects Ras and pERK levels after a single dose of FTS(A), Activated Ras (Ras-GTP), pERK, and total Ras were assayed in xenografts prepared from DA3 tumors removed from mice at the indicated time periods after treatment with FTS (40 mg/kg) or vehicle (0.5% CMC). Western blot analysis demonstrates the rapid effect of FTS on ERK phosphorylation and on Ras activation and expression in vivo. (B), Bar graph depicting the average intensity (%) of each treatment relative to the control group. Black Bars represent Ras-GTP, white Bars represent pERK, and gray Bars represent total Ras. The results showed that FTS inhibits Ras-GTP, pERK, and total Ras as early as 4 hours after treatment.
Mentions: The effect of FTS on Ras signaling was measured at the specified time points in tumors from mice treated with 40 mg/kg FTS. Western blot analysis (Fig. 4A) shows the effects of FTS on Ras-GTP, pERK, and total Ras in the tumors of mice sacrificed 4 hours (lanes 5 to 7), 8 hours (lanes 8 to 11), or 24 hours (lanes 12 to15) after FTS treatment compared to those of control mice treated with the vehicle alone (lanes 1 to 4). These results showed that Ras signaling in tumors mammary is inhibited from as early as 4 hours after treatment with FTS.

Bottom Line: In vitro, HGF/SF-activated Met increased Ras activity, Erk phosphorylation, cell motility and glucose uptake, but did not affect ATP.FTS inhibited basal and HGF/SF-induced signaling and cell motility, while further increasing glucose uptake and inhibiting ATP production.FTS did not affect basal blood-flow but abolished the HGF/SF effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University ; This work was done in partial fulfillment of the requirements for the Ph.D. degree of S.N.

ABSTRACT
High glucose uptake and increase blood flow is a characteristic of most metastatic tumors. Activation of Ras signaling increases glycolytic flux into lactate, de novo nucleic acid synthesis and uncoupling of ATP synthase from the proton gradient. Met tyrosine kinase receptor signaling upon activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF), increases glycolysis, oxidative phosporylation, oxygen consumption, and tumor blood volume. Ras is a key factor in Met signaling. Using the Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS), we investigated interplay between HGF/SF-Met-Ras signaling, metabolism, and tumor blood-flow regulation. In vitro, HGF/SF-activated Met increased Ras activity, Erk phosphorylation, cell motility and glucose uptake, but did not affect ATP. FTS inhibited basal and HGF/SF-induced signaling and cell motility, while further increasing glucose uptake and inhibiting ATP production. In vivo, HGF/SF rapidly increased tumor blood volume. FTS did not affect basal blood-flow but abolished the HGF/SF effect. Our results further demonstrate the complex interplay between growth-factor-receptor signaling and cellular and tumor metabolism, as reflected in blood flow. Inhibition of Ras signaling does not affect glucose consumption or basal tumor blood flow but dramatically decreases ATP synthesis and the HGF/SF induced increase in tumor blood volume. These findings demonstrate that the HGF/SF-Met-Ras pathway critically influences tumor-cell metabolism and tumor blood-flow regulation. This pathway could potentially be used to individualize tumor therapy based on functional molecular imaging, and for combined signaling/anti-metabolic targeted therapy.

No MeSH data available.


Related in: MedlinePlus