Understanding the mechanisms that underlie the antitumour activity of non-steroidal anti-inflammatory drugs (NSAIDs) against colorectal cancer will allow the development of more effective and specific chemopreventative agents. Modulation of the NF-jB pathway has been implicated as a key effector of the antitumour effect of aspirin, but the effects of non-aspirin NSAIDs on this pathway have yet to be fully defined. Here, we demonstrate that sulindac, sulindac sulfone and indomethacin activate the NF-jB pathway in colorectal cancer cells, as determined by western blot analysis of cytoplasmic levels of IjBa and immunocytochemical analysis of nuclear NFjB/RelA. Furthermore, we show that all of these NSAIDs induce nucleolar translocation of the RelA subunit of NFjB. Using RelA deleted for the previously described nucleolar localization signal, we demonstrate that this response is causally involved in the apoptotic effects of these agents. Finally, we demonstrate that NSAIDmediated nucleolar translocation of RelA is associated with downregulation of NF-jB-driven transcription and of the NF-jB target gene, ICAM-1. These data identify nucleolar translocation of RelA and the associated repression of the NF-jB-driven transcription as a central molecular mechanism of NSAID-mediated growth inhibition and apoptosis. As well as providing new understanding of the molecular determinants of RelA function, these findings also have relevance to the development of novel chemotherapeutic and chemopreventative agents.

Summary The present study was undertaken to compare the relationship between response to exogenous epidermal growth factor (EGF) and the expression of the EGF-receptor (EGF-R) in an androgen sensitive (LNCaP) and insensitive (DU145) prostate cancer cell line. Although both cell lines demonstrated a single EGF-R binding site of similar high affinities (mean dissociation constant (Kd) ± S.D. for DU145 = 1.0 ± 0.6 nmol 1-'; LNCaP = 2.8 2.2 nmol 1') the number of binding sites (RT) for the hormone insensitive DU145 cells (mean ± S.D. = 2.5 1.0 x 105 sites/cell) and 10-fold greater than that expressed in the androgen responsive LNCaP cell line (mean ± S.D. = 2.0 ± 1 x 104 sites/cell). Additionally exogenous EGF only minimally affected the growth and DNA synthesis of DU145 cells whereas LNCaP cells showed a significant response which was dose dependent. The autologous production of EGF-like molecules by DU145 cells is believed to reduce the cells needs for exogenous mitogens, thereby rendering the cells autostimulatory. Treatment of LNCaP cells with Mibolerone -a synthetic androgen -did not affect either the expression of the EGF receptor or the proliferative response observed with EGF. Western blot analysis, using monoclonal antibodies directed against the EGF receptor revealed a band of approximately 170 kD with DU 145 cell lysates but the LNCaP EGF receptor was not detected using this technique.In the early stages, prostate cancer growth is almost always androgen dependent, but eventually the tumour progresses to a more aggressive state in which growth is androgen independent (Griffiths et al., 1987). This transition is a major obstacle to successful treatment not only of carcinoma of the prostate but also in many other tumours originating from hormone responsive tissues (Hodges, 1979;Lippman, 1984 al., 1988;Traish & Wotiz, 1987;St-Arnaud et al., 1988). This complex relationship between steroid hormone and growth factors is not exclusive to the prostate gland, but has been observed in other hormone dependent organs. In breast cancer where a detailed study has been carried out on the interaction between oestrogens, progestins and growth factors and how they may act together to regulate cell proliferation, oestrogens have been shown to affect the production of TGF-(x (Dickson et al., 1986), and suppress the secretion of inhibitory growth factors (Knabbe et al., 1987) whereas progestins modulate epidermal growth factor receptor expression (Murphy et al., 1986).Although the evidence for steroid hormone regulation of growth factor content and activity in breast cancer is conCorrespondence: F.K. Habib. Received 1 May 1991; and in revised form 10 October 1991.vincing there are also suggestions that the progession to oestrogen independent breast cancer cell growth may be the result of a change in the activity of the growth factor or its receptor (King, 1990) and this highlights, once again, the complex nature and multiple pathways by which steroid hormone sensitive cells might be regulated by steroids. To further our under...

Summary Serum-free media conditioned by the androgen insensitive human prostate cancer cell line DU145 showed immunological transforming growth factor-a (TGFa) activity, as well as competing activity in epidermal growth factor (EGF) radioreceptor assays (RRA). Furthermore, there were factors in the conditioned media which inhibited and stimulated DNA synthesis by DU145

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