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

Abstract

Abstract. Sulforaphane, a well-characterised dietary isothiocyanate, has been demonstrated to be a potent anticarcinogenic agent in numerous cancer models, including in bladder cancer cells. In the present study, sulforaphane upregulated 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 sulforaphaneinduced up-regulation of GSTA1-1 and TR-1 and downregulation 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.

Sulforaphane and bladder cancer: a potential novel antitumor compound

“…So far, p38 has become a target for a series of anti-cancer drugs ( Yong et al, 2009 ). The activation of p38 MAPK plays an anti-BC role through various pathways, such as blocking the cell cycle process ( Yang et al, 2021 ), inducing cell apoptosis ( Zhang et al, 2014 ; Chen et al, 2022 ), inhibiting cell invasion and metastasis ( Kumar et al, 2010 ; Piao et al, 2021 ), and through the antioxidant response element (ARE) driving genes and COX-2 ( Shan et al, 2009 ; Shan et al, 2010 ). It is worth mentioning that SFN can significantly upregulate the expression of Nrf2-dependent enzymes (glutathione transferase and thioredoxin reductase) and downregulate the expression of COX-2, but p38 MAPK inhibitors can reverse this effect.…”

“…It is worth mentioning that SFN can significantly upregulate the expression of Nrf2-dependent enzymes (glutathione transferase and thioredoxin reductase) and downregulate the expression of COX-2, but p38 MAPK inhibitors can reverse this effect. The mechanism seems to be that SFN activates p38 MAPK, leading to the activation of Nrf2 mediated by p38 MAPK ( Shan et al, 2010 ).…”

“…So far, p38 has become a target for a series of anti-cancer drugs (Yong et al, 2009). The activation of p38 MAPK plays an anti-BC role Frontiers in Pharmacology frontiersin.org through various pathways, such as blocking the cell cycle process (Yang et al, 2021), inducing cell apoptosis (Zhang et al, 2014;Chen et al, 2022), inhibiting cell invasion and metastasis (Kumar et al, 2010;Piao et al, 2021), and through the antioxidant response element (ARE) driving genes and COX-2 (Shan et al, 2009;Shan et al, 2010).…”

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma

“…Although the influence of SFN on the MAPK pathway has been documented, respective experiments on bladder cancer cells are sparse. SFN upregulates the expression of two Nrf2-dependent enzymes, glutathione transferase (GSTA1-1) and thioredoxin reductase (TR-1), and downregulates COX-2 in T24 cells, which is closely associated with p38 MAPK activity [ 133 ]. Abbaoui and coworkers observed apoptosis and tumor weight reduction in murine UMUC3 xenografts exposed to SFN.…”

“…Data on MAPK signaling in bladder cancer are sparse and do not allow final conclusions as to how MAPK may communicate with ROS and Nrf2. Concerning the bladder cancer cell line T24, MAPK was shown to act as an upstream mediator of Nrf2 [ 133 ]. Inhibition of colorectal cancer cell proliferation and migration by SFN was induced by phosphorylating MAPK, which subsequently promoted Nrf2 accumulation and—in parallel—enhanced ROS [ 130 ].…”