Diet and P53 expression

Author: luca davicco
Date: 08/08/2014


A cura di Federico CERUTTI e Giulia GREMMO


Plants and animals are all-natural sources of all things good for us, right?
It turns out some of our favorite foods may do more harm than good while others may be healthy.

The food-chemistry and biology researchers tested the effects of some popular foods on cell cultures in the laboratory and discovered that a well-known repair gene, p53, which protects cells from becoming cancerous, was highly activated by several substances.

Various food elements caused a 30fold increase in p53-activity when added to the cells, such effect is similar to the after-math on the cancer-suppressing gene of a cytotoxic anticancer drug, a topoisomerase inhibitor , etoposide.

p53 is stimulated when the DNA is damaged, and the gene triggers a series of responses that attempt to repair the affected DNA. The greater the damage inflicted upon the DNA, the more p53 is activated, and researchers have come to regard p53 levels as a marker of DNA distress.


PEITC (phenethyl isothiocyante) is found in some cruciferous vegetables, such as watercress, broccoli and cabbage. PEITC has been studied for its potential for chemoprevention.
The researchers found that PEITC not only decreases the levels of mutated p53 protein in tumor cells, but also restores the "wild type" (with normal activity) to mutated p53. This led to a greater sensitivity to PEITC-induced cytotoxicity in tumor cell lines with mutant p53 rather than tumor cells with wild type p53, suggesting that the normal p53 checkpoint control pathways have been restored in the mutant p53-expressing tumor cells. This finding suggests that the PEITC and other compounds in the isothiocyante family could play an important role in both cancer prevention and oncological treatments with mutant p53.


Polyphenols likely induce intracellular oxidative stress and DNA damage with subsequent activation of kinases (MAPK, ATM, DNA-PK) responsible for p53 phosphorylation. Simultaneously, and also in response to DNA damage, acetylation of p53 or p73 have been described due to enhanced acetylase activity from p300 and/or to reduced deacetylase activity from SIRT1 or HDAC. In addition, p53 expression has been shown to be under the control of MDM2 as well as MTA1/NuRD, both factors being down regulated by polyphenols. Phosphorylation and acetylation, together with MDM2 inhibition result in p53, and to a less extend, p73 stabilization and sustained expression which programmed cell death pathways in cancer cells.


Scientists from Johns Hopkins Kimmel Cancer Center report in the journal Food and Chemical Toxicology that teas, coffees and “smoky flavoring” could damage our DNA at levels which resemble those caused by chemotherapic drugs.
Researches turned out that these foods and flavorings share some chemicals such as pyrogallol and gallic acid believed to be responsible for damaging the DNA and setting off p53. Pyrogallol is found in smoked foods as well as hair dye, tea, cigarette smoke, and coffee. Gallic acid is a type of pyrogallol and is primarily found in coffees and teas. It’s not clear how these agents act on DNA, but the harm is concerning enough to raise the alarm for p53 to attempt to correct the genetic mismatches.
Why would plants harbor such potentially damaging agents? It is possible they have a role in their protection from outside aggression, primarily from herbivores, looking for their next meal. Nature’ continuing evolution has led to plant production of poisons which on their end resulted in the animals development of various defense mechanisms against such poisons. This has been achieved up to a point that some of these initial poisons can be even considered nutrients or just food.


One nutrient that can affect p53 is vitamin C, or ascorbic acid. The ability to activate p53 in cancer cells proves important for cancer treatment. Many cancer cells inactivate p53, allowing the cells to evade death and continue proliferating up to becoming a tumor. The ability to activate p53 within these cells may halt cell proliferation, or even cause cancer cell death. Vitamin C is able to increase the levels of p53 within colon cancer cells, according to a study published by the Korean Society for Biochemistry and Molecular Biology in 2011. In addition, treating the cells with vitamin C was able to increase the efficacy of the chemotherapic drug cisplatin, inducing a more severe cancer cell death than using the drug alone.


Another nutrient with an effect on p53 is vitamin D. Similar to vitamin C, vitamin D may promote cancer death by activating p53. A study published in “Investigative Ophthalmology & Visual Science” in 2003 indicates that treating retinoblastoma cancer with vitamin D was able to increase the levels of p53, as well as other anti-cancer proteins within the cancer cells, leading to retinoblastoma cell death. Vitamin D might prove beneficial for controlling some types of cancer by activating p53.


An essential mineral with an effect on p53 is selenium. Selenium contributes to build up a number of proteins, and some of these selenium-containing proteins can interact with p53 in your cells. Specifically, the selenium-containing protein SeMet can activate p53 in response to genetic damage, helping the cell to repair its DNA, according to a study published in “Anticancer Research” in 2006. As a result, selenium may prevent cancer development. By allowing your cells to repair themselves, selenium fights the accumulation of genetic mutations required for cancer growth. The use of selenium to prevent some types of cancer is the subject of clinical trials, as of 2011, and the mineral might present a viable cancer treatment.


The processes of adding or removing phosphate from proteins is known to be a mechanism through which cells regulate protein function; these processes are called phosphorylation and dephosphorylation. Some chemicals found in hazardous waste may cause cancer not by inflicting damage directly on genetic material but rather by altering the function of proteins that control cell growth.
Several other laboratories have recently confirmed the evidence that chemicals such as benzene and perchloroethylene change the phosphorylation levels of two tumor suppressor gene products (like p53), possibly causing them to stimulate rather than suppress cell proliferation.


Researches identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly up regulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that up regulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, up regulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.

- Endothelial p53 expression is up regulated by a high-calorie diet
- p53-induced eNOS inhibition down regulates Pgc-1α expression in skeletal muscle
- Endothelial p53 down regulates Glut1 expression, leading to decreased glucose transport
- Inhibition of endothelial p53 expression improves dietary metabolic abnormalities


1. Huang C; Essential role of p53 in phenethyl isothiocyanate-induced apoptosis; Cancer Res. 1998
2. Xiao D, Singh SV; Phenethyl isothiocyanate-induced apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases;.Cancer Res. 2002
3. Yang YM, Conaway CC, Chiao JW, Wang CX, Amin S, Whysner J, Dai W, Reinhardt J, Chung FL; Inhibition of benzo(a)pyrene-induced lung tumorigenesis in A/J mice by dietary N-acetylcysteine conjugates of benzyl and phenethyl isothiocyanates during the postinitiation phase is associated with activation of mitogen-activated protein kinases and p53 activity and induction of apoptosis;Cancer Res. 2002
4. Lee JW, Cho MK; Phenethyl isothiocyanate induced apoptosis via down regulation of Bcl-2/XIAP and triggering of the mitochondrial pathway in MCF-7 cells; Arch Pharm Res. 2008 Dec
5. Dong Z ; Effects of food factors on signal transduction pathways; Biofactors. 2000
6. Hecht SS; Chemoprevention of lung cancer by isothiocyanates; Adv Exp Med Biol. 1996
7. Gu Q1, Hu C, Chen Q, Xia Y; Tea polyphenols prevent lung from preneoplastic lesions and effect p53 and bcl-2 gene expression in rat lung tissues; Int J Clin Exp Pathol. 2013 Jul 15
8. Gu Q, Hu C, Chen Q, Xia Y, Feng J, Yang H; Development of a rat model by 3,4-benzopyrene intra-pulmonary injection and evaluation of the effect of green tea drinking on p53 and bcl-2 expression in lung carcinoma; Cancer Detect Prev. 2009
9. Manna S, Mukherjee S, Roy A, Das S, Panda CK ; Tea polyphenols can restrict benzo[a]pyrene-induced lung carcinogenesis by altered expression of p53-associated genes and H-ras, c-myc and cyclin D1; Nutr Biochem. 2009 May
10. Gong Y, Han C, Che; Effect of tea polyphenols and tea pigments on the inhibition of precancerous liver lesions in rats; J.Nutr Cancer. 2000
11. Han C.Wei Sheng Yan Jiu; [Studies on tea and health]; 2011 Nov
12. Gu Q, Hu C, Chen Q, Xia Y, Feng J, Yang H. Zhongguo Fei Ai Za Zhi; Prevention of chinese green tea on 3,4-benzopyrene-induced lung cancer and its mechanism in animal mode; 2008
13. Wawrzyniak A1, Górnicka M, Hamułka; α-Tocopherol, ascorbic acid, and β-carotene protect against oxidative stress but reveal no direct influence on p53 expression in rats subjected to stress; Nutr Res. 2013 Oct
14. Asare GA, Ntombini B, Kew MC, Kahler-Venter CP, Nortey EN; Possible adverse effect of high delta-alpha-tocopherol intake on hepatic iron overload: enhanced production of vitamin C and the genotoxin, 8-hydroxy-2'- deoxyguanosine; Toxicol Mech Methods. 2010 Feb
15. Nakano M, Onodera A, Saito E, Tanabe M, Yajima K, Takahashi J, Nguyen VC; Effect of astaxanthin in combination with alpha-tocopherol or ascorbic acid against oxidative damage in diabetic ODS rats; J Nutr Sci Vitaminol (Tokyo). 2008 Aug
16. Schwedhelm E, Maas R, Troost R, Böger RH.; Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress; Clin Pharmacokinet. 2003
17. Maguire O1, Campbell MJ; Vitamin D and p53—differentiating their relationship in AML; Cancer Biol Ther. 2010 Aug 15
18. Thompson T, Danilenko M, Vassilev L, Studzinski GP; Tumor suppressor p53 status does not determine the differentiation-associated G₁ cell cycle arrest induced in leukemia cells by 1,25-dihydroxyvitamin D₃ and antioxidants; Cancer Biol Ther. 2010 Aug 15
19. Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M; Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML; Cell Cycle. 2006
20. Sugano T, Yamaizumi M.Tanpakushitsu Kakusan Koso; The conditions that induce tumor-suppressor protein p53;1995 Aug
21. Alwahaibi NY1, Budin SB, Mohamed JH; Absence of p53 gene expression in selenium molecular prevention of chemically induced hepatocarcinogenesis in rats; Saudi J Gastroenterol. 2011 Sep-Oct
22. Björkhem-Bergman L, Ekström L, Eriksson LC ; Review: Exploring anticarcinogenic agents in a rat hepatocarcinogenesis model--focus on selenium and statins; In Vivo. 2012 Jul-Aug
23. Allot EH1, Lysaght J, Cathcart MC, Donohoe CL ; MMP9 expression in oesophageal adenocarcinoma is upregulated with visceralobesity and is associated with poor tumour differentiation; Mol Carcinog. 2013 Feb


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