p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C

摘要

Abstract 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 p21waf1/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.