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p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C
According to WHO classification system, non-invasive urothelial carcinoma represents urothelial carcinoma in situ (CIS) and dysplasia. Dysplastic urothelium often progresses to CIS that further advances to urothelial carcinoma (UC). The strongest risk factor for UC is cigarette smoking. However, the...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615141/ https://www.ncbi.nlm.nih.gov/pubmed/28959653 http://dx.doi.org/10.1016/j.toxrep.2017.06.005 |
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author | Ganguly, Shinjini Chandra, Ayan Chattopadhyay, Dhruba J. Chatterjee, Indu B. |
author_facet | Ganguly, Shinjini Chandra, Ayan Chattopadhyay, Dhruba J. Chatterjee, Indu B. |
author_sort | Ganguly, Shinjini |
collection | PubMed |
description | According to WHO classification system, non-invasive urothelial carcinoma represents urothelial carcinoma in situ (CIS) and dysplasia. Dysplastic urothelium often progresses to CIS that further advances to urothelial carcinoma (UC). The strongest risk factor for UC is cigarette smoking. However, the pathogenesis of cigarette smoke (CS)-induced UC is poorly understood. Earlier we had shown that p-benzoquinone (p-BQ), a major toxic quinone derived from p-benzosemiquinone of CS in vivo, is a causative factor for various CS-induced diseases. Here, using a guinea pig model we showed that prolonged treatment with p-BQ led to non-invasive UC, specifically carcinoma in situ (CIS) of the renal pelvis and dysplasia in the ureter and bladder. The mechanisms of carcinogenesis were p-BQ-induced oxidative damage and apoptosis that were later suppressed and followed by activation of epidermal growth factor receptor, aberrant phosphorylation of intracellular tyrosine residues, activation of MAP kinase pathway and persistent growth signaling. This was accompanied by deregulation of cell cycle as shown by marked decrease in the expression of p21(waf1/cip1) and cyclin D1 proteins as well as hyperphosphorylation of pRb. UC has been characterised by histopathology and immunohistochemistry showing aberrant CK20, increased Ki-67, and marked p53 nuclear immunopositivity with uniformly negative labelling of CD44. Oral supplementation of vitamin C (30 mg/kg body weight/day) prevented CIS of the renal pelvis and dysplasia in the ureter and bladder. Since majority of non-invasive UC progresses to invasive cancer with increased risk of mortality, our preclinical study might help to devise effective strategies for early intervention of the disease. |
format | Online Article Text |
id | pubmed-5615141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-56151412017-09-28 p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C Ganguly, Shinjini Chandra, Ayan Chattopadhyay, Dhruba J. Chatterjee, Indu B. Toxicol Rep Article According to WHO classification system, non-invasive urothelial carcinoma represents urothelial carcinoma in situ (CIS) and dysplasia. Dysplastic urothelium often progresses to CIS that further advances to urothelial carcinoma (UC). The strongest risk factor for UC is cigarette smoking. However, the pathogenesis of cigarette smoke (CS)-induced UC is poorly understood. Earlier we had shown that p-benzoquinone (p-BQ), a major toxic quinone derived from p-benzosemiquinone of CS in vivo, is a causative factor for various CS-induced diseases. Here, using a guinea pig model we showed that prolonged treatment with p-BQ led to non-invasive UC, specifically carcinoma in situ (CIS) of the renal pelvis and dysplasia in the ureter and bladder. The mechanisms of carcinogenesis were p-BQ-induced oxidative damage and apoptosis that were later suppressed and followed by activation of epidermal growth factor receptor, aberrant phosphorylation of intracellular tyrosine residues, activation of MAP kinase pathway and persistent growth signaling. This was accompanied by deregulation of cell cycle as shown by marked decrease in the expression of p21(waf1/cip1) and cyclin D1 proteins as well as hyperphosphorylation of pRb. UC has been characterised by histopathology and immunohistochemistry showing aberrant CK20, increased Ki-67, and marked p53 nuclear immunopositivity with uniformly negative labelling of CD44. Oral supplementation of vitamin C (30 mg/kg body weight/day) prevented CIS of the renal pelvis and dysplasia in the ureter and bladder. Since majority of non-invasive UC progresses to invasive cancer with increased risk of mortality, our preclinical study might help to devise effective strategies for early intervention of the disease. Elsevier 2017-06-15 /pmc/articles/PMC5615141/ /pubmed/28959653 http://dx.doi.org/10.1016/j.toxrep.2017.06.005 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Ganguly, Shinjini Chandra, Ayan Chattopadhyay, Dhruba J. Chatterjee, Indu B. p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C |
title | p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C |
title_full | p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C |
title_fullStr | p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C |
title_full_unstemmed | p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C |
title_short | p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C |
title_sort | p-benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of egfr, map kinase activation and cell cycle deregulation: prevention by vitamin c |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615141/ https://www.ncbi.nlm.nih.gov/pubmed/28959653 http://dx.doi.org/10.1016/j.toxrep.2017.06.005 |
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