C-Raf controlled pathways in the protection of tumor cells from apoptosis.

The Raf serine-threonine kinase is upregulated in many human tumors and plays a pivotal role in tumor cell proliferation and survival. Abrogation of c-Raf expression by specific antisense oligonucleotides (Raf-AS-ODN) efficiently blocks tumor cell growth and induces apoptosis in human cancer cells. The signaling pathways and molecular mechanisms c-Raf utilizes to mediate the survival of tumor cells are, however, not well understood. Here we show that apoptosis triggered by Raf depletion cannot be overcome by ectopic Bcl-2 expression and occurs in the absence of cytochrome c release, arguing against a direct impact of c-Raf on mitochondrial pathways of apoptosis regulation. We also show that c-Raf depletion leads to a clearly decreased expression of different epidermal growth factor (EGF) receptor ligands, suggesting that the autocrine stimulation of an EGF receptor-mediated survival pathway might be involved in the blockade of tumor cell apoptotis by c-Raf.