BIOCHEMICAL

MEDICINE

AND

METABOLIC

BIOLOGY

47, 105-107

(1992)

EDITORIAL Role of Mitochondria in Oncogenesis The binding of hexokinase (HK) to the outer mitochondrial membrane varies in a tissue-specific and developmental stage-specific manner (reviewed in 1,2) and the activity of bound HK is particularly high in certain tumor cells (3). The Minireview by Golshani (4) in this issue, entitled “Insulin, Growth Factors, and Cancer Cell Energy Metabolism: An Hypothesis on Oncogene Action,” summarizes the evidence in support of a functional role for HK binding in tumor cell transformation. These concepts clearly have been influenced by the thinking of Dr. Samuel P. Bessman (5-9), the Founding Editor of this journal, and were stimulated by discussions between Golshani and Bessman, for the author is a medical student at the University of Southern California. This review, however, goes beyond these concepts to describe parallels between the actions of insulin and oncogenes, and generates testable working hypotheses regarding possible mechanisms underlying these similarities. Bessman’s HK-mitochondrial acceptor theory (5-7) has been substantiated by a variety of researchers and investigations (e.g., l-4,6-9). In addition to providing the energy to support cellular activity, the facilitation of HK activity by binding to the outer mitochondrial membrane (OMM) also provides the substrate for lipid and nucleotide biosynthesis required for the proliferation of neoplastic cells (3). There are unmistakable similarities between the cellular needs of embryonic-fetal cells and tumor cells. Several recent observations are pertinent to Golshani’s proposal (4) with respect to the mitochondrial associations of HK, as well as growth factors and protooncogenes. As she has noted, the HK activity bound to mitochondria in hepatoma cells can be strikingly elevated (3). The HK cDNA has been cloned from a highly glycolytic hepatoma cell line (10) and has an N-terminal domain identical to that observed in the human, rat, and bovine HKls (11-13). The N-terminal 15aminoacid sequence shared by these HKl proteins was incorporated into a reporter gene construct and was shown to be both necessary and sufficient for targeting the chimeric construct to the mitochondrial HKl receptor site of liver and hepatoma cells (14). As Golshani (4) noted, a feature common to many oncogenes is tyrosine kinase activity. Recent evidence indicates that HK has protein kinase activity, capable of autophosphorylation, as well as phosphorylation of other protein substrates, although it remains to be determined whether tyrosine and/or other amino acids are the site(s) of phosphorylation (15). Therefore, it has been 105 08854505/92 All

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observed that a sequence within the hepatoma HK can target this protein to the mitochondrial OMM and that bindable HKl has protein kinase activity. The mitochondrion has not been considered, classically, a site of action for growth factors or proto-oncogenes, but there is now evidence for the mitochondrial involvement of two such proteins. Transforming growth factor-p isoform 1 (TGFpl) appears to be localized, at least in part, to the mitochondria of heart and liver (16). The specific mitochondrial compartmentation and functional role of TGF-Pl in that organelle are yet to be elucidated. Bcl-2 is a proto-oncogene, and some would argue a bona fide oncogene, which is juxtaposed to the immunoglobulin heavy chain locus by the t(14;18) chromosomal translocation in human follicular B-cell lymphoma (17). Immunolocalization studies indicate that Bcl-2 is a component of the inner mitochondrial membrane (18). When overexpressed in a pro-B-lymphocyte cell line, Bcl-2 localized to mitochondria and blocked programmed cell death (18). These investigators concluded “that the main metabolic functions of the inner mitochondrial membrane, which include oxidative phosphorylation, electron and metabolite transport, are involved in the survival mechanism” (18). Therefore, it appears that these two proteins involved in tumor cell transformation, TGF-Pl and Bcl-2, have roles in mitochondrial function. These observations do not provide direct validation of Golshani’s concepts, but they most definitely are compatible with, and supportive of, her hypotheses. There is clear evidence that HK binding to mitochondria is associated with oncogenesis in liver cells and that this protein contains the targeting information for this binding within its N-terminal sequence. It also is clear that growth factors and protooncogenes are localized to mitochondria. Golshani’s review and these observations provide renewed validation for the very old concept that mitochondrial function is an important feature of oncogenesis. REFERENCES 1. Adams V, Griffin L, Towbin J, Gelb B, Worley K, McCabe ERB. Porin interaction with hexokinase and glycerol kinase: Metabolic microcompartmentation at the outer mitochondrial membrane. Biochem Med Mefab Biol45:271-291, 1991. 2. Griffin LD, Gelb BD, Adams V, McCabe ERB. Developmental expression of hexokinase 1 in the rat. Biochim Biophys Acfu, in press, 1991. 3. Arora KK, Pedersen PL. Functional significance of mitochondrial bound hexokinase in tumor cell metabolism-Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J Biol Chem X3:17,422-17,428, 1988. 4. Golshani S. Insulin, growth factors, and cancer cell energy metabolism: An hypothesis on oncogene action. Biochem Med Metub Biol. 47:108-115, 1992. 5. Bessman SP. A contribution to the mechanism of diabetes mellitus. In Fat Metabolism (Najjar VA, Ed.). Baltimore: Johns Hopkins Press, 1954, pp. 133-137. 6. Bessman SP. A molecular basis for the mechanism of insulin action. Am J Med 40~740-749, 1966. 7. Bessman SP. Hexokinase acceptor theory of insulin action-New evidence. Israel J Med Sci 8:344351, 1972. 8. Bessman SP, Geiger PJ. Compartmentation of hexokinase and creatine phosphokinase, cellular regulation, and insulin action. Curr Top Cell Regul 16:55-86, 1980. 9. Mohan C, Geiger PJ, Bessman SP. The intracellular site of action of insulin: The mitochondrial Krebs cycle. Curr Top Cell Rep1 30:105-142, 1989. 10. Arora KK, Fanciulli M, Pedersen PL. Glucose phosphorylation in tumor cells-Cloning, se-

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11. 12. 13. 14. 15. 16.

17. 18.

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quencing, and overexpression in active form of a full-length cDNA encoding a mitochondrial bindable form of hexokinase. .I Biol Chem 2655481-6488, 1990. Nishi S, Seino S, Bell GI. Human hexokinase: Sequences of amino- and carboxyl-terminal halves are homologous. Biochem Biophys Res Commun 157~937-943, 1988. Schwab DA, Wilson JE. Complete amino acid sequence of rat brain hexokinase, deduced from the cloned cDNA, and proposed structure of a mammalian hexokinase. Proc Nut1 Acad Sci USA 86~2563-2567, 1989. Griffin LD, Gelb BD, Wheeler DA, Davison D, Adams V, McCabe ERB. Mammalian hexokinase 1: Evolutionary conservation and structure to function analysis. Genomics 11:1014-1024, 1991. Gelb BD, Adams V, Jones SN, Griffin LD, MacGregor GR, McCabe ERB. Targeting of hexokinase 1 to liver and hepatoma mitochondria. Proc Natl Acud Sci USA 89:202-206, 1991. Adams V, Griffin LD, Gelb BD, McCabe ERB. Protein kinase activity of rat brain hexokinase. Biochem Biophys Res Commun 17’7:1101-1106, 1991. Heine UI, Burmester JK, Flanders KC, Danielpour D, Munoz EF, Roberts AB, Spom MB. Localization of transforming growth factor-@ in mitochondria of murine heart and liver. Cell Regul2:467-477, 1991. Strasser A, Harris AW, Bath ML, Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348~331-333, 1990. Hockenbery D, Nuriez G, Milliman C, Schreiber RD, Korsmeyer SJ. B&2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348~334-336, 1990. EDWARD R. B. MCCABE Editor

Role of mitochondria in oncogenesis.

BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY 47, 105-107 (1992) EDITORIAL Role of Mitochondria in Oncogenesis The binding of hexokinase (HK) to t...
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