Targeting COX-2/PGE(2) pathway in HIPK2 knockdown cancer cells: impact on dendritic cell maturation

Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and permit evasion of anti-tumour immune responses. Prostaglandin E2 (PGE2) is the most abundant prostaglandin found in colorectal cancer and favor tumor growth by stimulating proliferation, angiogenesis and invasiveness, and by inhibiting apoptosis. PGE2 also suppresses the immune responses and allows tumor cells to escape immunosurveillance by inducing local and systemic dendritic cells (DCs) dysfunction. Being able to reverse inhibitory mechanisms that in the tumor microenvironment affect DC activity may imply to have in some cases true tumor rejection. In this study we show that knockdown of homeodomain-interacting protein kinase-2 (HIPK2) in colon cancer cells resulted in cyclooxygenaese-2 (COX-2) upregulation and COX-2-derived PGE2 generation. At molecular level, COX-2 upregulation depended on hypoxia-inducible factor 1 (HIF-1) activity. We previously reported that zinc treatment inhibits HIF-1 activity. Here, zinc treatment of HIPK2 depleted cells inhibited HIF-1-induced COX2 expression and PGE2 production. At functional level, while conditioned media of HIPK2 depleted cells inhibited DC activation, in line with inhibition of DC maturation/activity by tumor-released factors, conditioned media from zinc-treated HIPK2 depleted cells efficiently restored DC maturation.