MEK inhibition enhances efficacy of bacillus Calmette-Guérin on bladder cancer cells by reducing release of toll-like receptor 2-activated antimicrobial peptides

Young Mi Whang, Su Bin Jin, Serk In Park, In Ho Chang

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)53168-53179
Number of pages12
JournalOncotarget
Volume8
Issue number32
DOIs
Publication statusPublished - 2017 Aug 8

Keywords

  • Antimicrobial peptides (AMPs)
  • Bacillus Calmette-Guérin (BCG)
  • Bladder cancer cells
  • MEK inhibitors
  • Toll-like receptors 2 and 4 (TLR2 and TLR4)

ASJC Scopus subject areas

  • Oncology

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