Modulation of p53 and c-myc in DMBA-induced mammary tumors by oral glutamine.
Previous studies established that oral glutamine (GLN) reduced tumor development in implantable and 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer models. This finding was associated with a decrease in tumor glutathione (GSH) levels, while maintaining normal gut, blood, and breast GSH. Alterations in GSH levels contribute to the control of apoptotic and cell cycle-regulating signaling. The aim of this study was to examine the role of dietary GLN on activation of p53 and c-myc, which play critical roles in cancer development and sensitivity to radiation and chemotherapy. Mammary gland carcinomas were induced in rats by DMBA. The rats were gavaged daily with GLN or water (controls), starting 1 wk prior DMBA-application and throughout the duration of the experiment (11 wk after DMBA). Tumor DNA was examined for mutations in p53 exons 5 and 6. Protein and mRNA levels of p53, p21(WAF1/CIP1), PTEN, IGF-IR, mdm2, and c-myc in tumors of GLN-supplemented rats were compared with those of the control rats (received water). The sequencing of p53 showed that it was wild type. Increased phosphorylation of p53, as well as higher mRNA and protein levels of p21(WAF1/CIP1), PTEN, and mdm2, and lower levels of IGF-IR were detected in tumors of GLN-supplemented rats vs. controls. Both phosphorylated c-myc and c-myc mRNA levels were reduced by GLN. The up-regulation of tumor p53 signaling and down-regulation of c-myc, in addition to previously established inhibition of Akt signaling in DMBA-breast cancer model, suggest that dietary GLN could be a useful approach for increasing the effectiveness of cancer treatment.
Todorova
Valentina K
VK
Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. todorovavalentinak@uams.edu
Kaufmann
Yihong
Y
Luo
Shaoke
S
Klimberg
V Suzanne
VS
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005973:Glutamine / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
D002273:Carcinogens; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D015127:9,10-Dimethyl-1,2-benzanthracene; D005978:Glutathione