p38 MAPK plays a distinct role in sulforaphane-induced up-regulation of ARE-dependent enzymes and down-regulation of COX-2 in human bladder cancer cells.
Sulforaphane, a well-characterised dietary isothiocyanate, has been demonstrated to be a potent anti-carcinogenic agent in numerous cancer models, including in bladder cancer cells. In the present study, sulforaphane up-regulated the expression of two Nrf2-dependent enzymes, glutathione transferase (GSTA1-1) and thioredoxin reductase (TR-1), and down-regulated cyclooxygenase 2 (COX-2) in human bladder cancer T24 cells. This action of sulforaphane was associated with the p38 MAPK activity. When a specific p38 MAPK inhibitor, SB202190, was used, both sulforaphane-induced up-regulation of GSTA1-1 and TR-1 and down-regulation of COX-2 were eliminated; in contrast, an activator of p38 MAPK, anisomycin, enhanced the effect of sulforaphane on modulation of GST, TR-1 and COX-2 expression. Moreover, it was established that anisomycin increased nuclear translocation of Nrf2, whereas SB202190 abrogated sulforaphane-induced Nrf2 translocation into the nucleus. In summary, these data suggest that p38 MAPK activation can regulate Nrf2-antioxidant response element (ARE)-driven enzymes and COX-2 expression, thereby facilitating the role of sulforaphane in cancer prevention. This study strongly supports the contention that p38 MAPK is a pivotal and efficient target of sulforaphane in the chemoprevention of bladder cancer.
Shan
Yujuan
Y
Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin 150081, PR China.
Wang
Xiaoxue
X
Wang
Wei
W
He
Canxia
C
Bao
Yongping
Y
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D053244:Osteoprotegerin; D013454:Sulfoxides; C506030:TNFRSF11B protein, human; D013861:Thiocyanates; D051546:Cyclooxygenase 2; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; D048051:p38 Mitogen-Activated Protein Kinases; C016766:sulforaphane