Proteasome inhibition increases expression of angiogenic chemokines in ovarian cancer cells through IKKβ, S536P‐p65 and EGR‐1 dependent pathways (935.1)

Abstract

Pro‐inflammatory and pro‐angiogenic chemokines interleukin‐8 (IL‐8), CCL2 (MCP‐1) and CXCL5 (ENA‐78) contribute to ovarian cancer progression through their induction of tumor cell proliferation, survival, angiogenesis and metastasis. Though proteasome inhibition by bortezomib (BZ) has been considered for the treatment of ovarian cancer, it has not been used because of its limited effectiveness; however, the responsible mechanisms remain elusive. Here, we show that proteasome inhibition dramatically increases the expression of IL‐8, CCL2 and CXCL5. The responsible mechanism involves an increased nuclear accumulation of IKKβ, and an increased recruitment of the nuclear IKKβ, p65 phosphorylated at S536, and transcription factor early growth response‐1 (EGR‐1) to the endogenous IL‐8, CCL2 and CXCL5 promoters. Co‐immunoprecipitation studies identified nuclear EGR‐1 associated with IKKβ and with p65, with preferential binding to S536P‐p65. Both IKKβ activity and EGR‐1 expression were required for the increased expression of IL‐8, CCL2 and CXCL5 induced by proteasome inhibition in ovarian cancer cells. These data indicate that the increased expression of IL‐8, CCL2 and CXCL5 may represent one of the underlying mechanisms responsible for the decreased effectiveness of proteasome inhibition in ovarian cancer treatment, and identify IKKβ and EGR‐1 as potential new targets in ovarian cancer therapies.Grant Funding Source: Supported by NIH grants AI085497 and CA173452 to I.V.