CROSS-TALK BETWEEN ERBB RECEPTORS, HH/GLI AND NF-kB SIGNALING PATHWAYS

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Accumulating evidence indicate that a complex interplay can occur between ErbB receptors, HH signaling and NF-kB pathway, and between HH and NF-kB signaling (Figure 2). It was reported that EGFR signaling via RAF/MEK/ERK modulates the target gene expression profile of GLIs in epidermal cells (43) and that SHH induces EGF-dependent matrix infiltration in HaCaT keratinocytes and that constitutive SHH expression is associated with increased phosphorylation of EGFR (44). Cooperation of EGFR signaling with HH/GLI was demonstrated to promote cancer cells transformation and proliferation. Eberl et al. identified a group of HH-EGFR cooperation response genes (i.e. JUN, SOX9, SOX2, FGF19, CXCR4), whose expression was directly regulated by GLI, but synergistically increased by EGFR signaling. These genes were important for determining the oncogenic phenotype of both BCC and tumor-initiating pancreatic cancer cells (45).

The PI3K/Akt and MAP kinase cascade (36,37) are at the crossroads of the cooperative EGFR/ErbB2 receptors-HH/GLI signaling pathways. Indeed, it was provided evidence that endogenous RAS-MEK and Akt signaling pathways regulate nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells (46). Riobò et al. demonstrated that PI3K and Akt activities are crucial for GLI-dependent SHH signaling. In addition, they provided evidence that stimulation of PI3K/Akt by IGF-I potentiates GLI transcriptional activity in the presence of low amounts of SHH (47). The same authors identified PKC-delta and MEK-1 as essential, positive regulators of GLI-mediated HH signaling (48). Schnidar et al. reported that EGFR signaling synergizes with GLI1 and GLI2 to selectively activate transcription of a subset of target genes via stimulation of RAS/RAF/MEK/ERK signaling; this induces JUN/activator protein 1 activation, which is crucial for oncogenic transformation. Further, these authors reported that combined inhibition of EGFR/MEK/ERK/JUN and HH/GLI signaling efficiently reduces growth of BCC (49). In addition, Seto et al. reported that PTCH expression was correlated with ERK1/2 phosphorylation and SHH expression in gastric cancers and that MAPK signaling regulates GLI activity via a SUFU-independent process (50). In agreement with the involvement of both HH and ErbB signaling in proliferation of androgen-independent prostate cancer cells, a synergistic effect of HH and ErbB inhibitors on prostate cancer cell growth was observed (51). In addition, the combined treatment with docetaxel and EGFR (gefitinib) and HH signaling (cyclopamine) inhibitors induced a higher rate of apoptotic death of prostate cancer cells compared with that obtained with individual agents (36).

A further level of cross-talk between ErbB receptors and HH signaling is likely to involve NF-kB. Hinohara et al. reported that heregulin, a ligand for ErbB3, induced mammosphere formation through a PI3K/NF-κB pathway in human breast cancer (52). It was also reported that IKKα plays an important role in controlling the ability of ErbB2 to activate NF-κB through the canonical pathway and that IKKα controls invasion of ErbB2 positive breast cancer cells (53). In addition, transactivation of ErbB2 provoked by TNF-α induced NF-κB activation and breast cancer cell proliferation (54). The activation of NF-κB is also capable of increasing ErbB2 activity. Indeed, it was shown that NF-κB activity enhances ErbB2-mediated mammary tumorigenesis in vivo by promoting both growth and survival via the stimulation of tumor vasculogenesis (55), and that IKKα has an important role on ErbB2-induced oncogenesis, providing signals that maintain mammary tumor-initiating cells (56). Moreover, activation of NF-kB in human breast cancer is confined  predominately to the estrogen receptor-negative subtype of cancers, particularly those that express EGFR and ErbB2 receptors (57). Indeed, ErbB2 activates NF-kB, and EGFR/ErbB2 overexpression participates or enhances the aberrant activity of NF-kB in cancer cells (53,58). It was earlier reported that ErbB2 activates NF-kB via a PI3K to Akt signaling pathway (59). Makino et al. reported that upregulation of IKKα and IKKβ by the integrin-linked kinase/Akt pathway is required for the ErbB2-mediated NF-kB anti-apoptotic pathway (60). Likewise, it was demonstrated that ErbB2 constitutively activates the Akt/NF-kB anti-apoptotic cascade to confer resistance to TNF on cancer cells (61).

A complex interplay arises also between PGE2 and growth factors mediated-signaling. Indeed, PGE2 can transactivate EGFR. In addition, it can stimulate the production of angiogenic growth factors, such as Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (bFGF), which in turn increase COX-2 expression. Signaling by PGE2 receptors further involves the activation of PI3K/Akt pathway and of the RAS/MAPK pathway, which is also able to enhance COX-2 expression, and upregulates the transcriptional activity of NF-kB, whose target genes include COX-2, whose expression is also controlled by AP-1 and their upstream kinases, MAPKs (29,33,62).

As for the interplay between NF-kB and HH signaling, it has been demonstrated that NF-kB can directly regulate SHH expression in vitro and in vivo, and promote pancreatic cancer cell proliferation and apoptosis resistance via the SHH pathway (63,64).