A highlight on Sonic hedgehog pathway

Abstract

Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview. Therefore, emerging studies are being conducted in order to find new inhibitors for Shh signaling pathway, which could be safely used in clinical trials. Shh can signal through a canonical and non-canonical way, and it also has important points of interaction with other pathways during brain tumorigenesis. So, a better knowledge of Shh signaling pathway opens an avenue of possibilities for the treatment of not only for brain tumors but also for other types of cancers. In this review, we will also highlight some clinical trials that use the Shh pathway as a target for treating brain cancer.

Keywords: Brain tumors; Canonical Shh signaling; Clinical-trials; Non-canonical Shh signaling; Sonic hedgehog pathway.

Fig. 1

The Canonical activation of Shh pathway in vertebrates. The activation occurs by ligand-dependent interaction when Shh binds to Ptch at the cell membrane. In response to this binding, Ptch no longer inhibits Smo, which accumulates at the PC and initiates the downstream signaling pathway cascade. So, Smo regulates the Gli processing and activation at the PC. When Gli is activated, it translocates to the nucleus, where it activates target genes. (Diagram by Carballo, VC). (Adapted from Robbins et al., 2012) [54]

Fig. 2

The non-canonical activation of Shh pathway. The non–canonical activation occurs through Gli-independent mechanisms and it can be of two types. A) Type I which modulates Ca²⁺ and actin cytoskeleton (left). When Shh binds the receptor Ptch, Smo is no longer inhibited and couple Gi proteins (G) and small GTPases RhoA and Rac1 activated. In addition, Smo stimulates calcium (Ca²⁺) release from the endoplasmic reticulum (ER) and PLC-γ-catalyzed the opening of IP3-dependent channels by the generation of IP3. B) Type II which is independent on Smo. When Shh binds Ptch, the interaction of Ptch with cyclin B1 is disrupted, leading to an increase in cell proliferation and survival (right). (Diagrams by Carballo, VC). (Adapted from Robbins et al., 2012) [54]

Fig. 3

The crosstalk between Shh pathway and others. Shh signaling pathway can crosstalk with several pathways, especially EGF, Wnt and TGF-β. Here we can observe the Shh signaling pathway in blue, the EGF pathway in orange, the Wnt pathway in, and TGF-β pathway in green. The crosstalk between these pathways and Shh occurs at different moments, and it becomes more important to understand this molecular interaction in order to search for new therapeutical drugs. (Diagrams by Carballo, VC). (Adapted from Matias et al., 2017; Berg and Soreide, 2012 and https://www.mycancergenome.org/content/molecular-medicine/pathways/TGF-beta-signaling) [128, 129]