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Interleukin‐6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression
Author(s) -
Lee Soo Ok,
Chun Jae Yeon,
Nadiminty Nagalakshmi,
Lou Wei,
Gao Allen C.
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20553
Subject(s) - lncap , autocrine signalling , neuroendocrine differentiation , cancer research , cell growth , prostate cancer , endocrinology , medicine , biology , androgen receptor , paracrine signalling , cancer cell , cancer , receptor , genetics
BACKGROUND Interleukin‐6 (IL‐6) has been implicated in the modulation of growth and differentiation in many cancers, and is associated with poor prognosis in renal cell carcinoma, ovarian cancer, lymphoma, melanoma, and prostate cancer. The effects of IL‐6 on the growth of LNCaP human prostate cancer cells are puzzling with some groups showing growth stimulation, while others showing growth inhibition. In this study, we investigated the discrepancy of the effects of IL‐6 on prostate cancer cells. METHODS Series of lower and higher passages of LNCaP cell sublines were generated by a long‐term exposure of LNCaP cells in IL‐6‐containing culture media. The characteristics of these cell sublines were analyzed and the potential roles of neuroendocrine (NE) differentiation and androgen receptor (AR) activation were examined. RESULTS We demonstrated that while short‐term treatment of IL‐6 inhibits LNCaP cell growth by a paracrine mechanism associated with NE differentiation, long‐term treatment of IL‐6 promotes LNCaP cell growth by an autocrine mechanism accompanied by an activation of AR signaling. In the lower passages (less than 28 passages) of LNCaP cells treated with IL‐6, the cell growth was severely retarded which is associated with NE‐like morphology and increased expression of NE markers such as neuronspecific enolase (NSE) and chromgranin A (ChgA), and loss of AR expression. However, in the higher passages (higher than 42 passages) of LNCaP cells treated with IL‐6, cells started to express endogenous IL‐6. At the same time, NE characteristics were disappeared, AR signaling was activated and cells growth was accelerated. Knocking down the AR activation of the higher passages of LNCaP cells abolished autocrine IL‐6‐induced growth stimulation. CONCLUSIONS These studies suggest that acquisition of endogenous IL‐6 production after prolong exposure of prostate cancer cells to IL‐6 may contribute to an autocrine cell growth stimulation. Furthermore, the transition of IL‐6 from a paracrine growth inhibitor to an autocrine growth stimulator suggests that IL‐6 plays an important role during prostate cancer progression, possibly androgen‐independent progression. Prostate 67: 764–773, 2007. © 2007 Wiley‐Liss, Inc.