Imiquimod induces apoptosis of squamous cell carcinoma (SCC) cells via regulation of A20

PLoS One. 2014 Apr 17;9(4):e95337. doi: 10.1371/journal.pone.0095337. eCollection 2014.

Abstract

Imiquimod, a nucleoside analogue of the imidazoquinoline family, is being used to treat various cutaneous cancers including squamous cell carcinoma (SCC). Imiquimod activates anti-tumor immunity via Toll-like receptor 7 (TLR7) in macrophage and other immune cells. Imiquimod can also affect tumor cells directly, regardless of its impact on immune system. In this study, we demonstrated that imiquimod induced apoptosis of SCC cells (SCC12) and A20 was involved in this process. When A20 was overexpressed, imiquimod-induced apoptosis was markedly inhibited. Conversely, knockdown of A20 potentiated imiquimod-induced apoptosis. Interestingly, A20 counteracted activation of c-Jun N-terminal kinase (JNK), suggesting that A20-regulated JNK activity was possible mechanism underlying imiquimod-induced apoptosis of SCC12 cells. Finally, imiquimod-induced apoptosis of SCC12 cells was taken place in a TLR7-independent manner. Our data provide new insight into the mechanism underlying imiquimod effect in cutaneous cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / pharmacology*
  • Apoptosis / drug effects*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Imiquimod
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • Aminoquinolines
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • JNK Mitogen-Activated Protein Kinases
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Imiquimod

Grants and funding

This study was supported by a grant from the National Research Foundation of Korea (NRF-2010-0023545). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.