View source for Diet and cancer

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==Overview==
[[Image:CancerDietPathway-wiki.jpg|left|thumb|250px|'''The [[methionine]] metabolism pathway'''. DHF, [[dihydrofolate]]; dSAM, decarboxylated [[S-adenosylmethionine]]; hCys, [[homocysteine]]; ME, [[methyl]] group; MetTR-1-P, 5-methylthioribose-1-phosphate; MT, [[methyltransferase]]; MTA, methylthioadenosine; MTHF, methylenetetrahydrofolate; SAH, [[S-adenosyl-L-homocysteine]]; SAM, [[S-adenosyl methionine]]; SUB, substrate.]]

Dietary patterns, foods, nutrients, and other dietary constituents are closely associated with the risk for several types of [[cancer]]. And while it is not yet possible to provide quantitative estimates of the overall risks, it has been estimated that 35 percent of [[cancer]] deaths may be related to dietary factors<ref>Doll R and Peto R: The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today.'' J Natl Cancer Inst'' (1981) 66:1191-1308</ref>.

==Reducing-risk factors==
Increasing evidence suggests that diets high in fiber-containing foods are associated with a reduced risk for [[cancer]], especially [[cancer]] of the colon<ref>Trock B, Lanza E and Greenwald P: [[Dietary fiber]], vegetables and colon cancer: Critical review and meta-analysis of the epidemiologic evidence. J Natl Cancer Inst (1990) 82:650-661</ref>.

A few studies have also shown a reduced risk for [[cancers]] of the breast, [[rectum]], oral cavity, [[pharynx]], stomach, and other sites with diets rich in fruits, vegetables and grain products <ref>Lanza E, Shankar S and Trock B: Dietary fiber. In Macronutrients: Investigating their role in cancer. (1992) (Micozzi MS, Moon TE, eds). New York: Marcell Dekker, Inc., 293-319</ref>. Numerous studies have found evidence that [[carotenoid]]s reduce the risk of some [[cancers]]. The evidence is particularly strong for lung [[cancer]]<ref>Ziegler RG: A review of [[epidemiologic]] evidence that [[carotenoids]] reduce the risk of [[cancer]]. (1989)J Nutr 119:116-122</ref>, even after taking smoking into account. [[Vitamin C]] is found in fruits, particularly citrus fruits and juices, and in green vegetables, as well as in some fortified foods. Of a group of [[epidemiologic]] studies investigating the role of [[vitamin C]], three-fourths found that [[vitamin C]], or fruit rich in [[vitamin C]], provides significant protection<ref>Block G: Vitamin C and cancer prevention: The epidemiologic evidence. Am J Clin Nutr (1991) 53:270S-282S</ref>.

==Contrary Evidence==
More recent studies have cast doubt on the claim that dietary fiber reduces the risk of colon cancer.<ref>[http://www.boston.com/news/nation/articles/2005/12/14/doubts_cast_on_fibers_effect_on_cancer/?rss_id=Boston+Globe+--+National+News The Boston Globe, "Doubts cast on fiber's effect on cancer" By Liz Kowalczyk, December 14,2005]</ref><ref>[http://www.intelihealth.com/IH/ihtIH/WSIHW000/333/7228/300409.html  Associated Press, "Study: Fiber Doesn't Prevent Cancer" October 13, 2000]</ref>  Regarding prostate cancer, a major 2002 study concluded that "A low-fat, high-fiber diet heavy in fruits and vegetables has no impact on PSA levels in men over a four-year period, and does not affect the incidence of prostate cancer."<ref>[http://www.scienceblog.com/community/older/2002/A/2002984.html  Science Blog, August 2002,From American Society of Clinical Oncology ]</ref>

The belief that dietary fiber prevents these cancers was based on epidemiological evidence showing a very low incidence in the developing world.  Dr. Denis Burkitt was the main proponent of this theory, and his 1979 best-selling book, "Don't Forget Fibre in Your Diet," was translated into nine languages.  Less well-known is his theory, mentioned in the book, that the squatting defecation posture used in the developing world is also a preventative factor, especially for colon diseases.  Now that his fiber theory has failed numerous attempts to confirm it, his other theory is gaining more attention as a new direction for research.

==Methionine metabolism==
Although numerous cellular mechanisms are involved in food intake, many investigations over the past decades have pointed out defections in the [[methionine]] metabolic pathway as cause of cancerogenesis<ref>Mikol, Y.B., Hoover, K.L., Creasia, D., Poirier, L.A. 1983. [[Carcinogenesis]]. 4: 1619-29</ref><ref>Ghoshal, A.K., Farber, E. 1984. [[Carcinogenesis]]. 5: 1367-70</ref>. For instance, deficiencies of the main dietary sources of [[methyl]] donors, [[methionine]] and [[choline]], lead to the formation of liver [[cancer]] in rodents<ref>Newmark, H.L., Yang, K., Lipkin, M., Kopelovich, L., Liu, Y., Fan, K., Shinozaki, H. 2001 [[Carcinogenesis]]. 11: 1871-5</ref><ref>Henning, S.M., Swendseid, M.E., Coulson, W.F. 1997. J. Nutr. 127: 30-6</ref>. [[Methionine]] is an essential [[amino acid]] that must be provided by dietary intake of [[proteins]] (meat) or [[methyl]] donors ([[choline]] and [[betaine]] found in beef, eggs and some vegetables). Assimilated methionine is transformed in [[S-adenosyl methionine]] (SAM) which is a key [[metabolite]] for [[polyamine]] synthesis, e.g. [[spermidine]], and [[cysteine]] formation (see the figure on the right). [[Methionine]] breakdown products are also recycled back into [[methionine]] by [[homocysteine]] remethylation and methylthioadenosine (MTA) conversion (see the figure on the right). Vitamins B6, B12, [[folic acid]] and [[choline]] are essential cofactors for these reactions. SAM is the substrate for [[methylation]] reactions catalyzed by DNA, RNA and protein [[methyltransferase]]s. 

[[Image:PRMTpathway.jpg|left|thumb|500px|Growth factor (GF) and steroid/retinoid activation of PRMT4.]]

The products of these reactions are [[methylated]] [[DNA]], [[RNA]] or [[proteins]] and S-adenosylhomocysteine (SAH). SAH has a negative feedback on its own production as an inhibitor of methyltransferase [[enzymes]]. Therefore SAM:SAH ratio directly regulates cellular methylation, whereas levels of vitamins B6, B12, folic acid and [[choline]] regulates indirectly the [[methylation]] state via the [[methionine]] metabolism cycle<ref>Caudill, M.A., Wang, J.C., Melnyk, S., Pogribny, I.P., Jernigan, S., Collins, M.D., Santos-Guzman, J., Swendseid, M.E., Cogger, E.A., James, S.J. 2001.  J. Nutr. 131(11): 2811-8</ref><ref>Poirier, L.A., Wise, C.K., Delongchamp, R.R., Sinha, R. 2001. Cancer Epidemiol. Biomarkers Prev. 10: 649-55</ref>. A near ubiquitous feature of [[cancer]] is a maladaption of the [[methionine]] [[metabolic pathway]] in response to genetic or environmental conditions resulting in depletion of SAM and/or SAM-dependent [[methylation]]. Whether it is deficiency in [[enzymes]] such as methylthioadenosine phosphorylase, [[methionine]]-dependency of [[cancer]] cells, high levels of [[polyamine]] synthesis in [[cancer]], or induction of [[cancer]] through a diet deprived of extrinsic [[methyl]] donors or enhanced in [[methylation]] inhibitors, [[tumor]] formation is strongly correlated with a decrease in levels of SAM in mice, rats and humans<ref>Prinz-Langenohl, R., Fohr, I., Pietrzik, K. 2001.  Eur. J. Nut. 40: 98-105</ref><ref>Van de Veyver, I.B. 2002. Annu. Rev. Nutr. 22: 2555-82</ref>. Many indirect and thinly circumstantial theories have been put forth related to [[methylation]] status of DNA or attacks upon the capacity for DNA mutation and repair. The discovery that [[methyltransferases]] whose activity would be directly influenced by SAM levels also act as [[tumor suppressor]]s potentially provides a more direct bridge. This has important ramifications for chemoprevention strategies as well as [[chemotherapy]]<ref>McBride, A.E., Silver, P.A. 2001. Cell. 106: 5-8</ref><ref>Huang, S. 2002. Nat. Rev. Cancer. 2: 469-76</ref><ref>Rea, S., Eisenbaber, F., O’Carroll, D., Strahl, B.D., Sun, Z.W., Schmid, M. Opravil, S., Mechtler, K.  Ponting, C.P., Allis, C.D., Jenuwein, T. 2000. Nature. 406: 593-9</ref><ref>Steele-Perkins, G., Fang, W., Yang, X.H., Van Gele, M., Carling, T., Gu, J., Buyse, I.M., Fletcher, J.A., Liu, J., Bronson, R., Chadwick, R.B., de la Chapelle, A., Zhang, X., Speleman, F., Huang, S.  Genes Dev. 2001. 15: 2250-62</ref>.

== Arginine methyltransferase ==
Protein [[arginine]] N-[[methyltransferase]]-4 (PRMT4) [[methylation]] of [[arginine]] residues within [[proteins]] plays a critical key role in transcriptional regulation (see the PRMT4 pathway on the left). PRMT4 binds to the classes of transcriptional activators known as p160 and CBP/p300<ref>Zika E, et al., Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression. Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16321-6</ref>. The modiﬁed forms of these [[proteins]] are involved in stimulation of [[gene expression]] via steroid [[hormone receptor]]s. Signiﬁcantly, PRMT4 methylates core [[histone]]s H3 and H4, which are also targets of the [[histone]] acetylase activity of CBP/p300 coactivators. PRMT4 recruitment [[chromatin]] by binding to coactivators increases [[histone]] [[methylation]] and enhances the accessibility of [[promoter]] regions for [[Transcription (genetics)|transcription]]. [[Methylation]] of the transcriptional coactivator CBP by PRMT4 inhibits binding to CREB and thereby partitions the limited cellular pool of CBP for [[steroid hormone]] receptor interaction.

==References==
{{reflist|2}}

==See also==
* [[DNA methyltransferase]]
* [[List of oncology-related terms]]
* [[Oncology]]
* [[American Cancer Society]]
* [[American Association for Cancer Research]]
* [[National Comprehensive Cancer Network]]

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[[Category:Nutrition]]
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[[Category:Oncology]]
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