Selina Raguz

Resistance to cancer chemotherapeutic treatment is a common phenomenon, especially in progressive disease. The generation of cellular models of drug resistance has been pivotal in unravelling the main effectors of resistance to traditional chemotherapy at the molecular level (i.e. intracellular drug inactivation, detoxifying systems, defects in DNA repair, apoptosis evasion, membrane transporters and cell adhesion). The development of targeted therapies has also been followed by resistance, reminiscent of an evolutionary arms race, as exemplified by imatinib and other BCR-ABL inhibitors for the treatment of chronic myelogenous leukaemia. Although traditionally associated with the last stages of the disease, recent findings with minimally transformed pretumorigenic primary human cells indicate that the ability to generate drug resistance arises early during the tumorigenic process, before the full transformation. Novel technologies, such as genome profiling, have in certain cases predicted the outcome of chemotherapy and undoubtedly have tremendous potential for the future. In addition, the novel cancer stem cell paradigm raises the prospect of cell-targeted therapies instead of treatment directed against the whole tumour.

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.