MK2 regulates the early stages of skin tumor promotion
Open Access
- 6 October 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 30 (12), 2100-2108
- https://doi.org/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 )-α-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 -α −/− 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 -α −/− mice and MK2 −/− mice, but most pronounced in TNF -α −/− 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 -α −/− 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.Keywords
This publication has 36 references indexed in Scilit:
- A cytokine-mediated link between innate immunity, inflammation, and cancerJCI Insight, 2007
- Inflammation, atrophy, and gastric cancerJCI Insight, 2007
- Innate Immunity Gone Awry: Linking Microbial Infections to Chronic Inflammation and CancerCell, 2006
- Paradoxical roles of the immune system during cancer developmentNature Reviews Cancer, 2006
- Prostate carcinogenesis and inflammation: emerging insightsCarcinogenesis: Integrative Cancer Research, 2004
- Inflammation and cancerNature, 2002
- Interfaces Between the Detection, Signaling, and Repair of DNA DamageScience, 2002
- Tumor necrosis factor or tumor promoting factor?Cytokine & Growth Factor Reviews, 2002
- Inflammation and cancer: back to Virchow?The Lancet, 2001
- Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesisNature Medicine, 1999