Raf-1 Addiction in Ras-Induced Skin Carcinogenesis

Abstract

Ras activation is common to many human cancers and promotes cell proliferation and survival by initiating multiple signaling cascades. Accordingly, Ras-transformed cells are generally considered too resourceful to become addicted to a single effector. In contrast to this tenet, we now demonstrate an absolute, cell autonomous requirement for Raf-1 in the development and maintenance of Ras-induced skin epidermis tumors. Mechanistically, Raf-1 functions as an endogenous inhibitor dimming the activity of the Rho-dependent kinase Rok-alpha in the context of a Ras-induced Raf-1:Rok-alpha complex. Raf-1-induced Rok-alpha inhibition allows the phosphorylation of STAT3 and Myc expression and promotes dedifferentiation in Ras-induced tumors. These data link the Raf-1:Rok-alpha complex to STAT3/Myc activation and delineate a pathway crucial for cell fate decision in Ras-induced tumorigenesis.

Raf kinases in cancer–roles and therapeutic opportunities

“…Recently, we have shown that endogenous C-Raf is essential to maintain an undifferentiated status in Ras-driven epidermal tumors. Conditional ablation of C-Raf results in rapid regression of established tumors through MEK/ERK-independent activation of a differentiation program induced by hyper-activation of the cytoskeleton-based kinase Rok-a (Ehrenreiter et al, 2009). These data show that Ras-driven tumors are addicted to non-oncogenic C-Raf, and offer proof of principle that differentiation (co)therapy may be feasible in solid tumors.…”

“…In the case of C-Raf, other targets potentially contributing to cell transformation have been proposed, such as the nuclear factor-kB pathway (Baumann et al, 2000), Rb (Kinkade et al, 2008) and BAD (Polzien et al, 2009), all reviewed by Niault and Baccarini (2010). In addition, C-Raf can inhibit apoptosis by binding to, and inhibiting, the stress-induced kinase ASK-1 (Chen et al, 2001) and the homolog of Drosophila's Hippo, the MST-2 kinase (O'Neill et al, 2004;Matallanas et al, 2007); and finally, C-Raf interferes, by direct binding, with the activity of the cytoskeleton-based Rho effector Rok-a (also known as ROCK2), resulting in defects in cell migration, apoptosis and differentiation (Ehrenreiter et al, 2005(Ehrenreiter et al, , 2009Piazzolla et al, 2005) (Figure 2). …”

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

“…Mouse strains and genotyping have been previously described (14). Strains were maintained on a 129Sv/Bl6 (F1) background.…”

p53 and NFκB: fresh breath in the cross talk

“…This situation is parallel to the situation in cancers which are addicted to activities of factors such as myc and Raf [8][9][10], and loss or diminishing the function of these factors causes the tumor cells to grow at a diminished pace. Myelan et al use nuclear accumulation of p65 as a measure of NFκB activation in this study.…”