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Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis.

Nowinski SM, Solmonson A, Rundhaug JE, Rho O, Cho J, Lago CU, Riley CL, Lee S, Kohno S, Dao CK, Nikawa T, Bratton SB, Wright CW, Fischer SM, DiGiovanni J, Mills EM - Nat Commun (2015)

Bottom Line: Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane.Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis.These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.

ABSTRACT
To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling.

No MeSH data available.


Related in: MedlinePlus

UCP3 overexpression impedes tumour promotion.(a) Timeline (in weeks) for Tg.AC tumour experiment. Sixteen-week old mice (Tg.AC, n=20, K5-UCP3/Tg.AC, n=20) were shaved dorsally and treated with bi-weekly applications of TPA (2.5 μg) for 2 weeks for a total of four treatments. Week ‘0' indicates first TPA application. (b) Tumour development in ‘pre-initiated' Tg.AC and bigenic K5-UCP3/Tg.AC mice indicating total papillomas per mouse, (c) % mice bearing papillomas, (d) total carcinomas per mouse, and (e) % mice bearing carcinomas. (f) Immunohistochemistry for BrdU labelled cells in wild-type FVB and K5-UCP3 epidermis following topical treatment with acetone (vehicle control), single (1 × ) or multiple (4 × ) treatments with 2.5 μg TPA. Scale bars, 50 microns. (g) Quantification of percentage of BrdU-positive labelled cells in the basal layer of the interfollicular epidermis. Error bars represent means+/−s.e.m. (n=3 animals per group). *Indicates significantly different from acetone control, same genotype (**P<0.01, ***P<0.0001, one way analysis of variance followed by Dunnett's post hoc analysis), † indicates significantly different from wild-type FVB, same treatment (†††P<0.0001, Student's t-test).
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f1: UCP3 overexpression impedes tumour promotion.(a) Timeline (in weeks) for Tg.AC tumour experiment. Sixteen-week old mice (Tg.AC, n=20, K5-UCP3/Tg.AC, n=20) were shaved dorsally and treated with bi-weekly applications of TPA (2.5 μg) for 2 weeks for a total of four treatments. Week ‘0' indicates first TPA application. (b) Tumour development in ‘pre-initiated' Tg.AC and bigenic K5-UCP3/Tg.AC mice indicating total papillomas per mouse, (c) % mice bearing papillomas, (d) total carcinomas per mouse, and (e) % mice bearing carcinomas. (f) Immunohistochemistry for BrdU labelled cells in wild-type FVB and K5-UCP3 epidermis following topical treatment with acetone (vehicle control), single (1 × ) or multiple (4 × ) treatments with 2.5 μg TPA. Scale bars, 50 microns. (g) Quantification of percentage of BrdU-positive labelled cells in the basal layer of the interfollicular epidermis. Error bars represent means+/−s.e.m. (n=3 animals per group). *Indicates significantly different from acetone control, same genotype (**P<0.01, ***P<0.0001, one way analysis of variance followed by Dunnett's post hoc analysis), † indicates significantly different from wild-type FVB, same treatment (†††P<0.0001, Student's t-test).

Mentions: To test whether UCP3 confers resistance to tumorigenesis mainly through effects on tumour initiation or tumour promotion, and to test the effect of UCP3 overexpression on tumour formation in a genetic model, we crossed K5-UCP3 animals with ‘pre-initiated' Tg.AC mice, which harbour an oncogenic v-Ha-Ras transgene19. In response to topical application of the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (treatment timeline Fig. 1a), Tg.AC mice rapidly formed tumours; however, bi-transgenic K5-UCP3/Tg.AC mice phenocopied the potent resistance to tumour formation observed in the K5-UCP3 background (Fig. 1b–e), indicating that UCP3 overexpression likely interferes with tumour promotion.


Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis.

Nowinski SM, Solmonson A, Rundhaug JE, Rho O, Cho J, Lago CU, Riley CL, Lee S, Kohno S, Dao CK, Nikawa T, Bratton SB, Wright CW, Fischer SM, DiGiovanni J, Mills EM - Nat Commun (2015)

UCP3 overexpression impedes tumour promotion.(a) Timeline (in weeks) for Tg.AC tumour experiment. Sixteen-week old mice (Tg.AC, n=20, K5-UCP3/Tg.AC, n=20) were shaved dorsally and treated with bi-weekly applications of TPA (2.5 μg) for 2 weeks for a total of four treatments. Week ‘0' indicates first TPA application. (b) Tumour development in ‘pre-initiated' Tg.AC and bigenic K5-UCP3/Tg.AC mice indicating total papillomas per mouse, (c) % mice bearing papillomas, (d) total carcinomas per mouse, and (e) % mice bearing carcinomas. (f) Immunohistochemistry for BrdU labelled cells in wild-type FVB and K5-UCP3 epidermis following topical treatment with acetone (vehicle control), single (1 × ) or multiple (4 × ) treatments with 2.5 μg TPA. Scale bars, 50 microns. (g) Quantification of percentage of BrdU-positive labelled cells in the basal layer of the interfollicular epidermis. Error bars represent means+/−s.e.m. (n=3 animals per group). *Indicates significantly different from acetone control, same genotype (**P<0.01, ***P<0.0001, one way analysis of variance followed by Dunnett's post hoc analysis), † indicates significantly different from wild-type FVB, same treatment (†††P<0.0001, Student's t-test).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4552083&req=5

f1: UCP3 overexpression impedes tumour promotion.(a) Timeline (in weeks) for Tg.AC tumour experiment. Sixteen-week old mice (Tg.AC, n=20, K5-UCP3/Tg.AC, n=20) were shaved dorsally and treated with bi-weekly applications of TPA (2.5 μg) for 2 weeks for a total of four treatments. Week ‘0' indicates first TPA application. (b) Tumour development in ‘pre-initiated' Tg.AC and bigenic K5-UCP3/Tg.AC mice indicating total papillomas per mouse, (c) % mice bearing papillomas, (d) total carcinomas per mouse, and (e) % mice bearing carcinomas. (f) Immunohistochemistry for BrdU labelled cells in wild-type FVB and K5-UCP3 epidermis following topical treatment with acetone (vehicle control), single (1 × ) or multiple (4 × ) treatments with 2.5 μg TPA. Scale bars, 50 microns. (g) Quantification of percentage of BrdU-positive labelled cells in the basal layer of the interfollicular epidermis. Error bars represent means+/−s.e.m. (n=3 animals per group). *Indicates significantly different from acetone control, same genotype (**P<0.01, ***P<0.0001, one way analysis of variance followed by Dunnett's post hoc analysis), † indicates significantly different from wild-type FVB, same treatment (†††P<0.0001, Student's t-test).
Mentions: To test whether UCP3 confers resistance to tumorigenesis mainly through effects on tumour initiation or tumour promotion, and to test the effect of UCP3 overexpression on tumour formation in a genetic model, we crossed K5-UCP3 animals with ‘pre-initiated' Tg.AC mice, which harbour an oncogenic v-Ha-Ras transgene19. In response to topical application of the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (treatment timeline Fig. 1a), Tg.AC mice rapidly formed tumours; however, bi-transgenic K5-UCP3/Tg.AC mice phenocopied the potent resistance to tumour formation observed in the K5-UCP3 background (Fig. 1b–e), indicating that UCP3 overexpression likely interferes with tumour promotion.

Bottom Line: Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane.Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis.These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.

ABSTRACT
To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling.

No MeSH data available.


Related in: MedlinePlus