Abstract 2690: MK2 pathway blockade inhibits inflammatory cytokine production and colorectal cancer growth and invasion

Abstract

Abstract Introduction: Colorectal cancer is the third most common malignancy diagnosed for both men and women in the United States of America. High levels of inflammatory cytokines in colorectal tumors cause increased growth and invasion and carry a higher risk of metastasis. Identifying new targets to control inflammation is important for developing improved treatment approaches. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a regulator of pro-inflammatory cytokines that may promote colorectal tumor progression. MK2 signaling is known to induce IL-1, IL-6, and TNF-α production. These pro-inflammatory cytokines are associated with CRC development, invasion, and metastasis. We hypothesized that the MK2 pathway could be an important component of CRC growth, invasion and tumor regrowth. Methods: To investigate this pathway, CT26 CRC cells were examined. Cells were flank-injected into Balb/c mice with and without MK2 inhibitor treatment. At day 19 after tumor injection, tumors were harvested and measured using calipers. Cytokines were quantitated by multiplex bead array in organ culture supernatants and in supernatants from tumor cells plated in fibronectin coated wells. In culture, tumor cell invasion was measured in scratch wound assays containing matrigel. Results: Treating CT26 cells with MK2 inhibitors markedly reduced tumor growth in mice by a mean of 60% compared to vehicle control treated cells. Inflammatory cytokines were also dramatically decreased with MK2 inhibition compared to controls by up to 80%. Cytokines affected included both known MK2 downstream cytokines (IL-1, IL-6, and TNF-α) and also chemokines such as MIP-1α and MCP-1 in both supernatants from cultured tumor cells and in organ culture supernatants. MK2 inhibition also decreased invasion of tumor cells in a cytokine dependent manner. Conclusions: The MK2 pathway regulates production of multiple pro-inflammatory cytokines in colorectal tumors, including several previously unreported chemokines. Inhibition of this pathway markedly decreases tumor growth and invasion. Thus, MK2 may be a promising tumor target to prevent colorectal cancer progression. Citation Format: Anita L. Ray, Amanda S. Peretti, Wade Johnson, Gregory Gan, Ellen J. Beswick. MK2 pathway blockade inhibits inflammatory cytokine production and colorectal cancer growth and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2690. doi:10.1158/1538-7445.AM2017-2690