Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1

Abstract

Although 40-60% of ovarian cancer (OVCA)s express estrogen receptor (ER)α, only a minor proportion of patients respond to anti-estrogen treatment with ER antagonist tamoxifen (TAM). The mechanism underlying TAM resistance in the course of OVCA progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of OVCA. Here we explore an association between IL-6 and TAM resistance. We demonstrate that both exogenous (a relatively short period of treatment with recombinant IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) induce TAM resistance in non-IL-6-expressing A2780 cells, while deleting of endogenous IL-6 expression in IL-6-overexpressing CAOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) promotes the sensitivity of these cells to TAM. Further investigation indicates that TAM resistance caused by IL-6 is associated with the alteration of ERα, ERβ and steroid hormone receptor coactivator (SRC)-1 expression levels, the protein interactions between SRC-1 and ERα, but not ERβ, as well as blockage of estrogen-induced ER receptor nuclear translocation. These results show that IL-6 secreted by OVCA cells may contribute to the refractoriness of these cells to TAM via ER isoforms and SRC-1. Overexpression of IL-6 not only plays an important role in OVCA progression but also contributes to TAM resistance. Our studies suggest that TAM-IL-6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone.

Keywords: Estrogen receptor (ER) isoforms; Interleukin-6 (IL-6); Ovarian cancer (OVCA); Steroid hormone receptor coactivator (SRC)-1; Tamoxifen (TAM) resistance.