MK2 regulates the early stages of skin tumor promotion

Carcinogenesis. 2009 Dec;30(12):2100-8. doi: 10.1093/carcin/bgp238.

Abstract

The association between inflammation and tumorigenesis is well recognized. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is known to play a pivotal role in inflammatory processes. Here, we studied the effect of MK2-deficiency and tumor necrosis factor (TNF)-alpha-deficiency on skin tumor development in mice using the two-stage chemical carcinogenesis model. We found that MK2(-/-) mice developed significantly fewer skin tumors compared with both TNF-alpha(-/-) and wild-type mice when induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). The TPA-induced inflammatory response was reduced in both, TNF-alpha(-/-) mice and MK2(-/-) mice, but most pronounced in TNF-alpha(-/-) mice, indicating that a reduced inflammatory response was not the only explanation for the inhibited tumorigenesis seen in MK2(-/-) mice. Interestingly, increased numbers of apoptotic cells were detected in the epidermis of MK2(-/-) mice compared with TNF-alpha(-/-) and wild-type mice, suggesting an additional role of MK2 in the regulation of apoptosis. This was further supported by: (i) increased levels of the tumor suppressor protein p53 in MK2(-/-) mice after DMBA/TPA treatment compared with controls, (ii) reduced phosphorylation (activation) of the negative p53 regulator, murine double minute 2 in MK2(-)(/-) mouse keratinocytes in vitro and (iii) a significant decrease in the DMBA/TPA induced apoptosis in cultured MK2(-/-) keratinocytes transfected with p53 small interfering RNA. Taken together, these findings demonstrate a dual role of MK2 in the early stages of tumor promotion through regulation of both the inflammatory response and apoptosis of DNA-damaged cells. These results also identify MK2 as a putative target for future skin carcinoma therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • DNA Damage
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Inflammation
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Keratinocytes / metabolism
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Small Interfering / metabolism
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology*
  • Tetradecanoylphorbol Acetate
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • Tetradecanoylphorbol Acetate