COX inhibitors modulate bFGF‐induced cell survival in MCF‐7 breast cancer cells

Abstract

Basic fibroblast growth factor (bFGF) serves as a modulator of survival in breast cancer cells. The mechanisms by which bFGF transduces the anti-apoptotic signal and interacts with COX inhibitors were investigated. bFGF reduced apoptosis in MCF-7 breast cancer cells and up-regulated the expression of mitocondrial Bcl-2, whereas COX inhibitors meloxicam (selective COX-2) and aspirin (non-selective), induced apoptosis. bFGF up-regulated survivin protein expression and induced cdc-2 phosphorylation moderately at early (2-6 h), and substantially at late (24 h), time-points. Survivin mRNA expression was up-regulated only at the later time-point. COX inhibitors prevented up-regulation of survivin protein expression at both 2 and 24 h and prevented early modest increases in cdc-2 phosphorylation. Up-regulation of survivin mRNA was not found to be modulated by the COX-2 inhibitor meloxicam. bFGF regulation of survivin expression was found to be ERK1/2 kinase dependent and bFGF-induced phosphorylation of c-raf was prevented by the COX-2 inhibitor. bFGF was, however, unable to induce COX-2 protein expression or modulate COX-2 activity in MCF-7 cells as evidenced by unaltered PGE(2) production. These results indicate that bFGF regulates survivin expression in MCF-7 breast cancer cells by signaling through an ERK1/2 dependent pathway. COX-2 inhibitors can modulate bFGF-induced survivin expression in a COX-2 independent manner.

Growth factor-dependent regulation of survivin by c-myc in human breast cancer

“…In the reporter assays using these, along with mutated c-myc response element oligos, we specifically manipulated the c-myc response element in relation to the survivin promoter and observed bFGF induction of survivin transcription. Following our previous observation that bFGF-induced regulation of survivin is MAPK dependent (Teh et al 2004), we have now shown that bFGF can induce c-myc protein expression in addition to directly phosphorylating c-myc in a MAPK-dependent manner. These findings subsequently led us to deduce the following survivin activation pathway whereby bFGF activates the MAPK cascade leading to phosphorylation of the transcription factor c-myc and ultimately resulting in elevated survivin gene expression.…”

“…In previous studies, we have demonstrated that the growth factor bFGF can up-regulate survivin expression in breast cancer cells, leading to increased cell proliferation with a concomitant decrease in apoptosis (Teh et al 2004). We and others have found that growth factor regulation of survivin expression is dependent on the MAP kinase signalling pathway (Carter et al 2001, Teh et al 2004.…”

“…In previous studies, we have shown that bFGF induces a rapid phosphorylation of c-raf in breast cancer cells and furthermore that bFGF-induced up-regulation of survivin protein can be inhibited by the MAP kinase antagonist PD98059, suggesting that bFGF regulates survivin expression in an ERK1/2-dependent manner through the phosphorylation of c-raf, independently of AKT (Teh et al 2004). To further evaluate the early and the late regulation of survivin following stimulation with bFGF in breast cancer cells, we have investigated the ability bFGF to modulate survivin protein and mRNA expression in the human breast cancer cell line, SK-BR-3.…”

“…In breast cancer, growth factors including bFGF have been associated with poor prognosis and a more angiogenic phenotype. Survivin, along with other members of the IAP gene family, has emerged as a unique regulator of cell death through its response to locally produced growth factors, such as bFGF, which we have previously shown activate the MAPK pathway leading to the up-regulation of genes associated with tumour progression, including survivin (Teh et al 2004). Survivin appears to be an important cancer therapeutic target, and modulation of survivin expression and/or function may provide rational approaches for cancer therapeutics.…”

“…Mek phosphorylates these transcription factors, which can then translocate to the nucleus where they may activate or suppress the transcription of target genes. We have previously shown that bFGF induces a rapid phosphorylation of c-raf in breast cancer cells and furthermore that bFGF-induced up-regulation of survivin protein can be inhibited by the MAPK/ERK Kinase (MEK) inhibitor PD98059, revealing that bFGF regulates survivin expression in an extracellular signalregulated Kinase (ERK)1/2-dependent manner through the phosphorylation of c-raf, independently of protein Kinase B (AKT) (Teh et al 2004).…”