Abstract
The involvement of fibroblast growth factor-2 (FGF-2) in the biology of small cell lung cancer (SCLC) has not previously been investigated. Here we report that FGF-2 prevented etoposide-induced apoptosis in H-510 SCLC cells. Phosphatidylinositol 3-kinase/protein kinase B signaling did not mediate this effect because FGF-2 failed to activate phosphatidylinositol 3-kinase or protein kinase B. In contrast, the mitogen-activated extracellularly regulated kinase kinase (MEK) was crucial for this response because its inhibition abolished the prosurvival properties of FGF-2. Moreover, in H-69 SCLC cells, the failure of FGF-2 to prevent etoposide-induced apoptosis correlated with uncoupling from MEK activation. However, the introduction of an activated MEK rendered these cells resistant to etoposide killing. Cell rescue relied on de novo protein synthesis, and the anti-apoptotic proteins Bcl-X(L) and Bcl-2 were up-regulated in a MEK-dependent fashion within 4 h of FGF-2 treatment. Contrary to previous reports, we found that this up-regulation occurred at the translational rather than the transcriptional level. Indeed, actinomycin D failed to prevent up-regulation of Bcl-X(L) and Bcl-2, and FGF-2 did not increase the mRNA levels or the stability of these proteins. The induction of the pro-apoptotic protein Bad by etoposide was also blocked by FGF-2 in a MEK-dependent fashion. Thus, MEK/extracellularly regulated kinase signaling is critical in the coordinate modulation of both pro- and anti-apoptotic Bcl-2 family members by FGF-2.
Highlights
The involvement of fibroblast growth factor-2 (FGF-2) in the biology of small cell lung cancer (SCLC) has not previously been investigated
fibroblast growth factors (FGFs)-2 Prevents Etoposide-induced Cell Death and Apoptotic Events in H-510 Cells—We have found that several SCLC cell lines including H-510 cells express FGFR1 and 2, which are known to bind FGF-2 with high affinity (25–29)
We initially tested whether the same concentration of FGF-2 could prevent etoposide-induced SCLC cell death
Summary
The involvement of fibroblast growth factor-2 (FGF-2) in the biology of small cell lung cancer (SCLC) has not previously been investigated. We show that FGF-2 signaling through MEK increases the levels of the anti-apoptotic members of the Bcl-2 family, Bcl-2 and Bcl-XL, and blocks etoposide-mediated induction of the pro-apoptotic protein Bad. These effects were When used at concentrations previously shown to block PI3K activity in SCLC cells (33), the addition of LY294002 alone resulted in reduced cell survival to an extent similar to that seen with etoposide (Fig. 2A).
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