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

作者：Wang Yue^*; Qu Ye; Zhang Xiao Lei; Xing Jie; Niu Xiu Long; Chen Xiao; Li Zong Min

来源：Molecular and Cellular Endocrinology, 2014, 382(2): 791-803.

DOI：10.1016/j.mce.2013.10.029

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

Although 40-60% of ovarian cancer (OVCA)s express estrogen receptor (ER)alpha, 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 ER alpha, ER beta and steroid hormone receptor coactivator (SRC)-1 expression levels, the protein interactions between SRC-1 and ER alpha, but not ER beta, 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 1L-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.

• 出版日期2014-2-15