MEK inhibition enhances efficacy of bacillus Calmette-Guérin on bladder cancer cells by reducing release of Toll-like receptor 2-activated antimicrobial peptides
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Young Mi Whang1,*, Su Bin Jin1,*, Serk In Park2,3,** and In Ho Chang1,**
1Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea
2Department of Biochemistry and Molecular Biology and BK21 Plus Program, Korea University College of Medicine, Seoul, Korea
3Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
*Young Mi Whang and Su Bin Jin contributed equally to this work
**In Ho Chang and Serk In Park contributed equally to this work
In Ho Chang, email: [email protected]
Serk In Park, email: [email protected]
Keywords: bacillus Calmette-Guérin (BCG), Toll-like receptors 2 and 4 (TLR2 and TLR4), antimicrobial peptides (AMPs), MEK inhibitors, bladder cancer cells
Received: November 30, 2016 Accepted: May 12, 2017 Published: May 26, 2017
Bacillus Calmette-Guérin (BCG) is one of the standard treatment options for non-muscle-invasive bladder cancer. The details of the biological defense mechanisms against BCG remain unclear. Here, we investigated whether BCG-induced release of antimicrobial peptides (AMPs; e.g., human β-defensin-2, -3, and cathelicidin) is involved with mitogen-activated protein kinase (MAPK) pathways, and investigated the enhanced anticancer effect of BCG through the down-regulation of Toll-like receptors (TLRs) and MAPK pathways in bladder cancer cells. BCG-infected bladder cancer cells produced AMPs as a defense mechanism against BCG, which were reduced by MEK inhibitors by blocking phosphorylation of extracellular signal-regulated kinase (ERK1/2 or MEK) and c-Jun. MEK inhibitors enhanced inhibition of bladder cancer cell growth by decreased binding of c-Jun, p65 and Pol II to the activated protein-1 promoter. Knockdown of TLR2 and TLR4 reduced ERK phosphorylation. Knockdown of TLR 2 decreased release of AMPs, which was similar to the efficacy of MEK inhibitor on BCG-infected cells. BCG-infected bladder cancer cells were more prone to induction of AMP release following TLR2 activation via ERK and c-Jun pathway mediators. In conclusion, our data suggest that the BCG-induced release of AMPs in bladder cancer cells is a promising molecular target for enhancing the immunotherapeutic efficacy of BCG in bladder cancer patients.
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