Multistage carcinogenesis involves multiple genes and multiple mechanisms

Weinstein, I. Bernard; Gattoni‐Celli, Sebastiano; Kirschmeier, Paul T.; Lambert, Michael; Hsiao, Wen-Luan Wendy; Backer, Joseph M.; Jeffrey, Alan M.

doi:10.1002/jcp.1041210416

Cited by 91 publications

(56 citation statements)

References 75 publications

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“…One model has been presented in the literature that involves the C4 hydroxyl group of the phorbol esters as an important binding moiety; in this model the C4, C9, and C20 oxygens of phorbol esters were matched with the diglyceride oxygens (10)(11)(12). This model is not consistent with the fact that 4-deoxyphorbol esters are active tumor promoters and PKC activators (10,13,(17)(18)(19). However, by using the conformation of diglyceride discussed above, an excellent match consistent with all the published structure-activity observations can be identified between phorbol esters and diglyceride (Fig.…”

Section: Discussionmentioning

confidence: 80%

“…However, these models are seriously flawed because they all ascribe a key role to the C4 hydroxyl group in the phorbol esters and to the C3 hydroxyl group of debromoaplysiatoxin (DAT). However, 4-deoxyphorbol esters lacking this hydroxyl group are still active tumor promoters (10,13,(17)(18)(19), and, as will be shown in this paper, 3-deoxy-DAT lacking the C3 hydroxyl group is also still a potent PKC activator.…”

mentioning

confidence: 60%

“…The most important observation is that 3-deoxy-DAT is as active as DAT itself.' All the hypotheses advanced to date for the structural correlation of aplysiatoxins with diglyceride or phorbol esters include the C3 hydroxy oxygen of aplysiatoxin (13,15,16,19,24). However, the work reported here firmly establishes that the C3 hydrophilic center is not important for activation.…”

Section: Discussionmentioning

confidence: 99%

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Structural basis of protein kinase C activation by tumor promoters.

Nakamura

Kishi

Pajares

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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Protein kinase C (PKC) is an important enzyme that helps govern cell metabolism and growth. The enzyme is physiologically activated when an (S)-diglyceride binds to its own regulatory domain. The saturable binding site of the regulatory domain can also be bound by any of a group of structurally diverse tumor promoters, including debromoaplysiatoxins (DATs), phorbol esters, ingenols, teleocidins, and bryostatins. The question of how the same binding site can be the target of these structurally diverse molecules is of considerable importance and is addressed in this article. The relatively rigid structure of DAT and the fact that it possesses a diglyceride moiety renders it an ideal starting template. Structure-activity studies with PKC reveal that the C29 but not the C30 stereocenter of DAT is critical for activity. Furthermore, 3-deoxy-DAT and DAT are equipotent as PKC activators, hence the C3 hydroxyl group of DAT is not critical for activity. Straightforward structural considerations show that the C30 hydroxyl group ofDAT matches the C3 hydroxyl group of diglyceride, the C29 stereocenter of DAT matches the C2 stereocenter of (S)-diglyceride, and the C1 ester moiety of DAT matches the C2 ester moiety of diglyceride. Based on these studies and on published structure-activity observations on other tumor promoters, a structural hypothesis is developed to account for the chemical mechanism of tumor promoter action. Experimentally testable predictions are made concerning the interactions with PKC of several classes of tumor PKC activators.A central question in the mechanism of protein kinase C (PKC) action is concerned with the nature of the activation process. This physiologically important enzyme is activated when a diglyceride binds to an effector site on its regulatory domain (1, 2). The diglyceride itself is produced as a consequence of the regulated hydrolysis of phosphatidylinositol phosphates by a specific phospholipase (3). The interaction of PKC with diglyceride is stoichiometric (4) and stereospecific, with the (S)-enantiomer being active (5, 6). The specificity of this process has been further probed with diglyceride analogs (7-9). These studies have shown an unusual degree of specificity directed toward the glycerol backbone and the hydrophilic moieties of the diglycerides. The strict specificity shown toward the diglycerides must be contrasted with the behavior of PKC toward the tumor promoters, including phorbol esters, ingenols, aplysiatoxins, and teleocidins (see Fig. 7). All these structurally diverse molecules share PKC as their common target and appear to function by binding to and activating the enzyme permanently, whereas the diglycerides bind and activate temporarily (10)(11)(12).Given that it is highly likely that the various tumor promoters and active diglycerides bind to the same site on the regulatory domain ofPKC, it must be possible to demonstrate structural commonalities in these various agents. Several models, generated by various computer-driven modeling protocols, have alread...

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis of protein kinase C activation by tumor promoters.

Nakamura

Kishi

Pajares

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…Because the potential risk of cancer has been a primary concern of ELF-EMF exposures, understanding both the mechanisms of carcinogenesis and the potential relevance of our in vitro system must be delineated. Carcinogenesis is a multistage, multimechanism process (37,38), consisting of initiation, promotion, and progression phases. The weight of the evidence appears to have negated the possibility of a mutagenic or initiating potential of ELF-EMF fields (39).…”

Section: Discussionmentioning

confidence: 99%

Effect of electromagnetic field exposure on chemically induced differentiation of friend erythroleukemia cells.

Chen

Upham

Sun

et al. 2000

Environ Health Perspect

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Whether exposure of humans to extremely low frequency electromagnetic fields (ELF-EMF) can cause cancer is controversial and therefore needs further research. We used a Friend erythroleukemia cell line that can be chemically induced to differentiate to determine whether ELF-EMF could alter proliferation and differentiation in these cells in a manner similar to that of a chemical tumor promoter. Exposure of this cell line to 60 Hz ELF-EMF resulted in a dose dependent inhibition of differentiation, with maximal inhibition peaking at 40% and 40 mG (4 microT). ELF-EMF at 10 mG (1.0 microT) and 25 mG (2.5 microT) inhibited differentiation at 0 and 20%, respectively. ELF-EMF at 1.0 (100) and 10.0 G (1,000 microT) stimulated cell proliferation 50% above the sham-treated cells. The activity of telomerase, a marker of undifferentiated cells, decreased 100[times] when the cells were induced to differentiate under sham conditions, but when the cells were exposed to 0.5 G (50 microT) there was only a 10[times] decrease. In summary, ELF-EMF can partially block the differentiation of Friend erythroleukemia cells, and this results in a larger population of cells remaining in the undifferentiated, proliferative state, which is similar to the published results of Friend erythroleukemia cells treated with chemical-tumor promoters.

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“…3,4 Therein, the first conceptual problem emerges. Referring to a chemical that produces a cancer as a "carcinogen" implies that it produces all the three steps of carcinogenesis, which have different operational characteristics, such as being, either irreversible or potentially interruptible or reversible, creates the first problem.…”

Section: Introductionmentioning

confidence: 99%

Reflections on the use of 10 IARC carcinogenic characteristics for an objective approach to identifying and organizing results from certain mechanistic studies

Trosko

2017

Toxicology Research and Application

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To find a scientifically based method for evaluating mechanistic data related to risks to human beings, a new protocol for identifying, organizing, and summarizing mechanistic data for decision-making on cancer hazard identification was proposed by the International Agency for Research on Cancer and by an international working group of multidisciplinary experts. This Commentary examined the 10 key carcinogens' characteristics proposed in the context of several paradigms assumed in the using of these 10 characteristics. These characteristics were assumed to represent a "carcinogen's" mechanism of action but what was ignored were characteristics of the mechanisms of the "initiation," "promotion," and "progression" carcinogenic process. Challenges were made to the interpretation of genotoxicity data as well as from concepts and findings related to the promotion phase and the role of adult human stem cells. Reliance of interpretation of "genotoxicity" data (molecular-DNA lesions in DNA; induction of free radicals/oxidative stress markers; phenotypic surrogates of gene mutations), as well as from lesions in genomic versus mitochondrial DNA, or in the target cells for the carcinogenic process in either in vitro cultures or in vivo tissues, makes this "objective" use of the data questionable. A challenge to the "dedifferentiation" hypothesis of cancer was made. Because of an agent being misclassified as "genotoxic"-rather than an "epigenetic"-agent (which works by threshold levels; can be blocked; and must be present at critical times during development and at regular, sustained chronic exposures) could lead to unwise policy decisions.

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Multistage carcinogenesis involves multiple genes and multiple mechanisms

Cited by 91 publications

References 75 publications

Structural basis of protein kinase C activation by tumor promoters.

Structural basis of protein kinase C activation by tumor promoters.

Effect of electromagnetic field exposure on chemically induced differentiation of friend erythroleukemia cells.

Reflections on the use of 10 IARC carcinogenic characteristics for an objective approach to identifying and organizing results from certain mechanistic studies

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