Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Abstract

Colorectal cancer (CRC) development and progression is associated with chronic inflammation. We have identified the MAPK-activated protein kinase 2 (MK2) pathway as a primary mediator of inflammation in CRC. MK2 signaling promotes production of proinflammatory cytokines IL-1β, IL-6 and TNF-α. These cytokines have been implicated in tumor growth, invasion and metastasis. For the first time, we investigate whether MK2 inhibition can improve outcome in two mouse models of CRC. In our azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated CRC, MK2 inhibitor treatment eliminated murine tumor development. Using the implanted, syngeneic murine CRC cell line CT26, we observe significant tumor volume reduction following MK2 inhibition. Tumor cells treated with MK2 inhibitors produced 80% less IL-1β, IL-6 and TNF-α and demonstrated decreased invasion. Replenishment of downstream proinflammatory MK2-mediated cytokines (IL-1β, IL-6 and TNF-α) to tumors led to restoration of tumor proliferation and rapid tumor regrowth. These results demonstrate the importance of MK2 in driving proinflammatory cytokine production, its relevance to in vivo tumor proliferation and invasion. Inhibition of MK2 may represent an attractive therapeutic target to suppress tumor growth and progression in patients.

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

“…Our studies and others have shown an important role for MK2 in the tumor microenvironment [2,3,13]. Cytokine/ chemokine regulation of other cytokines/chemokines is generally believed to be complex, particularly in inflammation.…”

“…Since we found in mouse models that MK2 activation is increased by inflammatory cytokine production [3], here we examined gene expression in a panel of gastric cancer samples. MK2 gene expression was examined by quantitative Real Time (qRT) PCR and scrutinized according tumor stage.…”

“…We have been studying the Map kinase-activated protein kinase 2 (MK2) pathway as a potential target for inflammation and tumor growth in gastrointestinal cancers in mouse models [2,3], and here we examine the relevance of this pathway to human gastric cancer. MK2 is downstream of p38 MAP-kinase and is associated with DNA damage and regulation of inflammatory cytokine production, specifically, IL-1β, IL-6, and TNF-α [3][4][5]. These cytokines are known to have pro-tumorigenic properties.…”

Crocin has pharmacological effects against the pathological behavior of colon cancer cells by interacting with the STAT3 signaling pathway

“…MIP2, MCP-1 and IL-8 are reported to promote the aggregation of neutrophils to tumor sites, and thus are deemed biomarkers for the chemotactic and metastatic capability of cells (30)(31)(32)(33). As stimulating factors, IL-6, IL-1β and TNF-α further promote the transformation from inflammation to colon cancer (12,13). The results showed that crocin treatment reduced the levels of MIP2, MCP-1, IL-8, IL-6, IL-1β and TNF-α in the supernatant from cultured HCT116 cells.…”

“…Inflammation is involved in the occurrence and development of colon cancer (11). For example, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α are involved in all aspects of colon cancer (12,13). However, the anticancer and anti-inflammatory functions of crocin in colon cancer cells have not been investigated.…”