Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased IGF-induced tyrosine phosphorylation and reduction in IGFBPs
Clinical Biochemistry Department, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Endocrinology
(Impact Factor: 4.5).
04/1996; 137(3):1089-95. DOI: 10.1210/en.137.3.1089
A significant increase in endometrial cancer incidence in tamoxifen-treated breast cancer patients has been reported in many recent studies. The major growth stimulators of endometrial tumors are estrogens, but paradoxically, tamoxifen, a known antiestrogen, also stimulates their growth. The mode of action of estrogen can be partially explained by the modulation of insulin-like growth factor (IGF) autocrine or paracrine action. The purpose of the present study was to examine the involvement of the IGF system in the tamoxifen-stimulated growth of Ishikawa endometrial cancer cells by quantitating the IGF-I receptors and their phosphorylation, as well as membrane associated and secreted IGF-binding proteins (IGFBPs). Tamoxifen did not affect the number or affinity of IGF-I receptors. On the other hand, tamoxifen, similar to estradiol, increased IGF-I-stimulated tyrosine phosphorylation of cellular substrates. In contrast, in MCF-7 mammary cancer cells, tamoxifen reduced IGF-induced tyrosine phosphorylation in the presence of estradiol. The pure antiestrogen LY156758 did not affect Ishikawa basal cell growth but inhibited estradiol- and tamoxifen-induced growth. Growth inhibition by LY156758 of tamoxifen and estradiol-stimulated cells was accompanied by a corresponding inhibition of IGF-stimulated tyrosine phosphorylation. Tamoxifen caused a 3-fold decrease in membrane-associated IGFBPs. Moreover, a reduction in soluble IGFBPs was also observed, making the IGF peptides more available to the receptors. A parallel decrease in IGFBP-3 mRNA was also detected. These experiments suggest that tamoxifen, like estradiol, directly sensitizes endometrial cancer cells to the effects of IGFs that act through the type I receptor. Furthermore, the decrease in IGFBPs and the increase in tyrosine phosphorylation in the presence of tamoxifen provides a molecular mechanism that accounts for the uterotropic effects that are seen with tamoxifen therapy.
Available from: link.springer.com
- "We found that the functions of protein phosphorylation in all the enriched KEGG pathways are supported by previous studies. Table 2 Enriched KEGG pathways for selected human proteins KEGG ID P value KEGG Term References 04110 0.000 Cell cycle Bradbury et al., 1974; Lee et al., 1988; Atherton-Fessler et al., 1993; Lew and Kornbluth, 1996; Matsuoka et al., 1998; Konishi et al., 2002; Yu and Chen, 2004 05215 0.000 Prostate cancer Haldar et al., 1996; Lin et al., 2002; El Sheikh et al., 2004; Jiang et al., 2004; Kreisberg et al., 2004; Jaggi et al., 2005; Chen et al., 2006; Shimada et al., 2006; Mahajan et al., 2007; Bianchini et al., 2008 04520 0.000 Adherens junction Volberg et al., 1992; Collares-Buzato et al., 1998; Andriopoulou et al., 1999; Gomez et al., 1999; Tinsley et al., 1999; Serres et al., 2000; Shasby et al., 2002 04910 0.000 Insulin signaling pathway Myers et al., 1998; Zick, 2001; Aguirre et al., 2002; Andreozzi et al., 2004; Ueki et al., 2004; Gual et al., 2005; McManus et al., 2005; Ueno et al., 2005; D'Alessandris et al., 2007; Wang et al., 2007 03013 0.000 RNA transport Aubol et al., 2004; Topisirovic et al., 2004 03040 0.000 Spliceosome Mermoud et al., 1994; Wang et al., 1999; Mathew et al., 2008 05200 0.000 Pathways in cancer Foster and Wimalasena, 1996; Itoh et al., 2002; Viglietto et al., 2002; Vivanco and Sawyers, 2002; Altomare et al., 2004; Viatour et al., 2005; Cicenas, 2008 05213 0.000 Endometrial cancer Kleinman et al., 1996; Kanamori et al., 2001; Terakawa et al., 2003 05220 0.000 Chronic myeloid leukemia Oda et al., 1996; Coluccia et al., 2007; Jilani et al., 2008; Jalkanen et al., 2011; Zhang et al., 2012 04810 0.000 Regulation of actin cytoskeleton Arber et al., 1998; Sumi et al., 1999; Head et al., 2003; Vardouli et al., 2005; Park et al., 2012 04114 0.000 Oocyte meiosis Dekel, 1996; Fan et al., 2002; Wang et al., 2006a; Liang et al., 2007; Swain and Smith, 2007 05223 0.000 Non-small cell lung cancer Lee et al., 2002; Cappuzzo et al., 2004; Kim et al., 2005; Tang et al., 2006; Tsurutani et al., 2006 "
[Show abstract] [Hide abstract]
ABSTRACT: Protein phosphorylation is a ubiquitous protein post-translational modification, which plays an important role in cellular signaling systems underlying various physiological and pathological processes. Current in silico methods mainly focused on the prediction of phosphorylation sites, but rare methods considered whether a phosphorylation site is functional or not. Since functional phosphorylation sites are more valuable for further experimental research and a proportion of phosphorylation sites have no direct functional effects, the prediction of functional phosphorylation sites is quite necessary for this research area. Previous studies have shown that functional phosphorylation sites are more conserved than non-functional phosphorylation sites in evolution. Thus, in our method, we developed a web server by integrating existing phosphorylation site prediction methods, as well as both absolute and relative evolutionary conservation scores to predict the most likely functional phosphorylation sites. Using our method, we predicted the most likely functional sites of the human, rat and mouse proteomes and built a database for the predicted sites. By the analysis of overall prediction results, we demonstrated that protein phosphorylation plays an important role in all the enriched KEGG pathways. By the analysis of protein-specific prediction results, we demonstrated the usefulness of our method for individual protein studies. Our method would help to characterize the most likely functional phosphorylation sites for further studies in this research area.
Protein & Cell 07/2012; 3(9):675-90. DOI:10.1007/s13238-012-2048-z · 3.25 Impact Factor
Available from: Branko Radaković
- "Tamoxifen caused a 3-fold decrease in IGF BPs. Moreover, a reduction in soluble IGF BPs was also observed, making the IGF peptides more available to the receptors . "
[Show abstract] [Hide abstract]
ABSTRACT: To investigate the consequences of IGF proteins dysfunction in development of endometrial adenocarcinomas.
The expression of IGF 2 and IGF 1R was correlated with the expression of IGF 2R and apoptosis rate in 59 human endometrial adenocarcinomas, 10 endometrial hyperplasias and 7 normal tissues. The presence of mutations in the IGF 2R gene was followed in 46 adenocarcinomas. We also examined the effect of IGF 1 receptor blockage on cancer cell proliferation. In groups of either IGF 2-positive or IGF 2-negative tumors (stages III and IV) the expression of IGF 1 and IGF 1R was correlated with cell proliferation index and telomerase activity.
The expression of IGF 2 and IGF 1R was much higher in malignant tissue of stages III and IV than in tumors of stages I and II and normal or hyperplastic endometrium. This correlated with a decreased apoptosis rate and IGF 2R expression. Eight adenocarcinomas expressed biallelic mutation of the IGF 2R gene. The specific inhibition of IGF 1R and IGF 2 decreased tumor cell proliferation in IGF 2/IGF 1R-positive tumors. Furthermore, the positive correlation between increased expression of IGF 1 and IGF 1R proteins and increased telomerase activity and cell proliferation index was found in both IGF 2-negative and IGF 2-positive tumors.
Our data suggest that IGF 1, IGF 2 and their receptors are involved in the progression of endometrial adenocarcinomas. As cancer cell proliferation can be abrogated by blocking mRNA or protein products of these genes, tumors with extensive involvement of the IGF 2 pathway would be candidates for the therapeutics strategies aimed at interference with this pathway.
Gynecologic Oncology 06/2007; 105(3):727-35. DOI:10.1016/j.ygyno.2007.02.012 · 3.77 Impact Factor
Available from: Eric Adriaenssens
- "Cells were incubated for 3 days with or without the different stimuli as described in the figure legends. As an indirect measure of growth, the 3-[4,5-dimethylthiazol 2-yl] 2,5-diphenyltetrazolium bromide (MTT) assay was used as previously described . "
[Show abstract] [Hide abstract]
ABSTRACT: Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. With a view to investigating the molecular mechanisms implicated, we studied the effect of estradiol on the expression of proteins implicated in the insulin-like growth factor signalling pathway. Estradiol dose- and time-dependently increased the expression of insulin receptor substrate-1 and the p85/p110 subunits of phosphatidylinositol 3-kinase but did not change those of ERK2 and Akt/PKB. ICI 182,780 did not inhibit estradiol-induced IRS-1 and p85 expression. Moreover, two distinct estradiol-BSA conjugate compounds were as effective as estradiol in inducing IRS-1 and p85/p110 expression indicating the possible implication of an estradiol membrane receptor. Comparative analysis of steroids-depleted and steroids-treated cells showed that IGF-I only stimulates cell growth in the latter condition. Nevertheless, expression of a constitutively active form of PI 3-kinase in steroid-depleted cells triggers proliferation. These results demonstrate that estradiol positively regulates essential proteins of the IGF signalling pathway and put in evidence that phosphatidylinositol 3-kinase plays a central role in the synergistic pro-proliferative action of estradiol and IGF-I.
Biochemical and Biophysical Research Communications 01/2007; 350(4):916-21. DOI:10.1016/j.bbrc.2006.09.116 · 2.30 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.