Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2007

Open Access 01-12-2007 | Research

The oncoprotein H-RasV12 increases mitochondrial metabolism

Authors: Sucheta Telang, Andrew N Lane, Kristin K Nelson, Sengodagounder Arumugam, Jason Chesney

Published in: Molecular Cancer | Issue 1/2007

Login to get access

Abstract

Background

Neoplastic cells increase glycolysis in order to produce anabolic precursors and energy within the hypoxic environment of a tumor. Ras signaling is activated in several cancers and has been found to regulate metabolism by enhancing glycolytic flux to lactate. We examined the effects of sequential immortalization and H-RasV12-transformation of human bronchial epithelial cells on the anabolic fate of fully-labeled 13C-glucose-derived carbons using two-dimensional total correlated spectroscopic analysis-nuclear magnetic resonance spectroscopy (2D TOCSY-NMR).

Results

We found that the introduction of activated H-RasV12 into immortalized human bronchial epithelial cells unexpectedly increased tricarboxylic acid cycle activity as measured by the direct conversion of 13C-glucose carbons into the anabolic substrates glutamate/glutamine, aspartate and uridine. We then observed that immortalization and H-RasV12-transformation of bronchial epithelial cells caused a stepwise increase in oxygen consumption, a global measure of electron transport chain activity. Importantly, ectopic expression of H-RasV12 sensitized immortalized cells to the ATP-depleting and cytotoxic effects of electron transport perturbation using the complex I inhibitor rotenone.

Conclusion

Taken together, these data indicate that the oncoprotein H-RasV12 increases mitochondrial metabolism and provide new rationale for the targeting of the tricarboxylic acid cycle and electron transport chain as anti-neoplastic strategies.
Appendix
Available only for authorised users
Literature
1.
Biaglow JE, Cerniglia G, Tuttle S, Bakanauskas V, Stevens C, McKenna G: Effect of oncogene transformation of rat embryo cells on cellular oxygen consumption and glycolysis. Biochem Biophys Res Commun. 1997, 235 (3): 739-742. 10.1006/bbrc.1997.6835CrossRefPubMed
2.
Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004, 4 (11): 891-899. 10.1038/nrc1478CrossRefPubMed
3.
Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK: Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res. 2002, 8 (4): 1284-1291.PubMed
4.
Medina RA, Owen GI: Glucose transporters: expression, regulation and cancer. Biol Res. 2002, 35 (1): 9-26.CrossRefPubMed
5.
Portais JC, Voisin P, Merle M, Canioni P: Glucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR. Biochimie. 1996, 78 (3): 155-164. 10.1016/0300-9084(96)89500-9CrossRefPubMed
6.
Shim H, Chun YS, Lewis BC, Dang CV: A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci U S A. 1998, 95 (4): 1511-1516. 10.1073/pnas.95.4.1511PubMedCentralCrossRefPubMed
7.
Walenta S, Schroeder T, Mueller-Klieser W: Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem. 2004, 11 (16): 2195-2204.CrossRefPubMed
8.
Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ: Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. Neoplasia. 2005, 7 (4): 324-330. 10.1593/neo.04430PubMedCentralCrossRefPubMed
9.
Warburg O: On the metabolism of cancer cells. Biochemische Zeitschrift. 1924, 152: 319-344.
10.
Guppy M, Leedman P, Zu X, Russell V: Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002, 364 (Pt 1): 309-315.PubMedCentralCrossRefPubMed
11.
Roberts PJ, Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007, 26 (22): 3291-3310. 10.1038/sj.onc.1210422CrossRefPubMed
12.
Kole HK, Resnick RJ, Van Doren M, Racker E: Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts. Arch Biochem Biophys. 1991, 286 (2): 586-590. 10.1016/0003-9861(91)90084-VCrossRefPubMed
13.
Racker E, Resnick RJ, Feldman R: Glycolysis and methylaminoisobutyrate uptake in rat-1 cells transfected with ras or myc oncogenes. Proc Natl Acad Sci U S A. 1985, 82 (11): 3535-3538. 10.1073/pnas.82.11.3535PubMedCentralCrossRefPubMed
14.
Ramanathan A, Wang C, Schreiber SL: Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci U S A. 2005, 102 (17): 5992-5997. 10.1073/pnas.0502267102PubMedCentralCrossRefPubMed
15.
Telang S, Yalcin A, Clem AL, Bucala R, Lane AN, Eaton JW, Chesney J: Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene. 2006, 25 (55): 7225-7234. 10.1038/sj.onc.1209709CrossRefPubMed
16.
Soejima K, Fang W, Rollins BJ: DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras. Oncogene. 2003, 22 (30): 4723-4733. 10.1038/sj.onc.1206510CrossRefPubMed
17.
Fan TW, Higashi RM, Lane AN: Integrating metabolomics and transcriptomics for probing SE anticancer mechanisms. Drug Metab Rev. 2006, 38 (4): 707-732. 10.1080/03602530600959599CrossRefPubMed
18.
Fan TW, Lane AN, Higashi RM: The promise of metabolomics in cancer molecular therapeutics. Curr Opin Mol Ther. 2004, 6 (6): 584-592.PubMed
19.
Greenhouse WV, Lehninger AL: Occurrence of the malate-aspartate shuttle in various tumor types. Cancer Res. 1976, 36 (4): 1392-1396.PubMed
20.
Arai T, Ogawa T, Nakamura M, Hosoya M, Ohnishi Y: Changes in hepatic enzyme activities in transgenic mice carrying human prototype c-Ha-ras gene treated with diethylnitrosamine. J Vet Med Sci. 2002, 64 (11): 1065-1067. 10.1292/jvms.64.1065CrossRefPubMed
21.
Okada A, Takehara H, Yoshida K, Nishi M, Miyake H, Kita Y, Komi N: Increased aspartate and glutamate levels in both gastric and colon cancer tissues. Tokushima J Exp Med. 1993, 40 (1-2): 19-25.PubMed
22.
Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J: RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007, 282 (19): 14056-14064. 10.1074/jbc.M700906200PubMedCentralCrossRefPubMed
23.
Chen EI, Hewel J, Krueger JS, Tiraby C, Weber MR, Kralli A, Becker K, Yates JR, Felding-Habermann B: Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res. 2007, 67 (4): 1472-1486. 10.1158/0008-5472.CAN-06-3137CrossRefPubMed
24.
Czerniak B, Chen R, Tuziak T, Markiewski M, Kram A, Gorczyca W, Deitch D, Herz F, Koss LG: Expression of ras oncogene p21 protein in relation to regional spread of human breast carcinomas. Cancer. 1989, 63 (10): 2008-2013. 10.1002/1097-0142(19890515)63:10<2008::AID-CNCR2820631024>3.0.CO;2-DCrossRefPubMed
25.
Czerniak B, Herz F, Wersto RP, Alster P, Puszkin E, Schwarz E, Koss LG: Quantitation of oncogene products by computer-assisted image analysis and flow cytometry. J Histochem Cytochem. 1990, 38 (4): 463-466.CrossRefPubMed
26.
Miyakis S, Sourvinos G, Spandidos DA: Differential expression and mutation of the ras family genes in human breast cancer. Biochem Biophys Res Commun. 1998, 251 (2): 609-612. 10.1006/bbrc.1998.9527CrossRefPubMed
27.
Liu H, Hu YP, Savaraj N, Priebe W, Lampidis TJ: Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001, 40 (18): 5542-5547. 10.1021/bi002426wCrossRefPubMed
28.
Maher JC, Krishan A, Lampidis TJ: Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol. 2004, 53 (2): 116-122. 10.1007/s00280-003-0724-7CrossRefPubMed
29.
Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P: Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005, 65 (2): 613-621.PubMed
30.
31.
Fan TW: Structure-based profiling of Metabolites and Isotopomers by NMR. Progress in Nuclear Magnetic Resonance Spectroscopy. 2007
32.
Lane AN, Fan TW: Determination of positional isotopomers in metabolites. Metabolomics. 2007, 3: 79-86. 10.1007/s11306-006-0047-x.CrossRef
33.
Fan TW: Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells. Metabolomics. 2005, 1 (4): 1-15.
34.
Fan TWM: Metabolite profiling by one- and two-dimensional NMR analysis of complex mixtures. Progress in Nuclear Magnetic Resonance Spectroscopy. 1996, 28: 161-219.CrossRef
35.
36.
37.
von Heimburg D, Hemmrich K, Zachariah S, Staiger H, Pallua N: Oxygen consumption in undifferentiated versus differentiated adipogenic mesenchymal precursor cells. Respir Physiol Neurobiol. 2005, 146 (2-3): 107-116. 10.1016/j.resp.2004.12.013CrossRefPubMed
Metadata
Title
The oncoprotein H-RasV12 increases mitochondrial metabolism
Authors
Sucheta Telang
Andrew N Lane
Kristin K Nelson
Sengodagounder Arumugam
Jason Chesney
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2007
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-6-77

Other articles of this Issue 1/2007

Molecular Cancer 1/2007 Go to the issue

Book review

Book Review of "The Molecular Biology of Cancer" by Stella Pelengaris, Michael Khan (Editors)

Research

Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines

Research

Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles

Research

Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression

Research

Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model

Research

Identification of a human TFPI-2 splice variant that is upregulated in human tumor tissues
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits