The dark side of IL-1: role in prostate cancer progression

Abstract

Abstract IL-1 is a pro-inflammatory cytokine essential for host defense against pathogens, but its role in cancer progression remains understudied. Recently our lab identified the IL-1 pathway as a molecular mechanism responsible for myeloid-driven prostate cancer development. Here, we report that IL-1 signaling in tumor cells drives prostate cancer progression. To identify the contribution of IL-1 signaling in prostate cancer progression, we downregulated expression of IL1R1 (the only known functional receptor for IL-1α/β) using shRNA or Crisr/Cas9 in androgen-sensitive (LNCaP) and androgen-independent (PC-3M) prostate cancer cell lines. We found that IL-1α inhibited expression of androgen receptor in LNCaP while suppression of IL-1 signaling abrogated this effect. The expression of neuron-specific enolase which was shown to be a prognostic marker associated with poor survival outcome was significantly reduced in PC-3M cells lacking IL1R1. Downregulation of IL-1 signaling in cancer cells resulted in significant inhibition of prostate tumor growth while no effect on cell proliferation was detected. We established this phenomenon and found several possible mechanisms underlying it. We found that knocking down of IL1R1 in cancer cells resulted in suppression of mTOR and ACC signaling in tumors. TUNEL staining revealed increased number of apoptotic cells in shIL1R1-PC-3M tumors. Tumors lacking IL1R1 were characterized by impaired vascularization which was accompanied by reduced COX-2, VEGF-A and IL-8 expression. Taken together, our findings indicate that downregulation of IL-1 signaling modifies prostate cancer cell phenotype and suppresses tumor growth.