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

8 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

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation (NRF) of the Republic of Korea (2015R1A1A1A0500110 and 2015R1A2A1A15054364 to I.H.C., 2015R1C1A1A01051508 to S.I.P., and 2016R1D1A1B03933826 to Y.M.W.); Korea University Research Grant (S.I.P.); the Korea Health Technology R&D Project (HI17C0710 to I.H.C.); and the National Cancer Center (Grant No. 1720140 to S.I.P.), the Ministry of Health and Welfare of Korea.

Publisher Copyright:
© Whang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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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