The Role of Smoothened in Cancer

Abstract

Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.

Keywords: Hedgehog signaling pathway; Smoothened; cancer stem cells.

Figure 1

Canonical Hedgehog (HH) signaling pathway. (a) OFF state: PTCH inhibits Smoothened (SMO) activity, and transcription factor GLI and SUFU are proteolytic by proteasome. The GLI repressor form (GLI^R) binds to target genes and there is no target gene expression. (b) ON state: HH ligands binds to PTCH to weaken the inhibition of SMO. SMO can then activate transcription factor GLI. The SUFU is removed from the binding to GLI. Therefore, GLI activator form (GLI^A) to regulate target gene expression related to Bcl2 gene for cell survival, c-Myc gene for cell proliferation, MMPs genes for migration/invasion, FoxF1 gene for angiogenesis and PROM1 for cancer stem cells.

Figure 2

Noncanonical HH signaling pathway. SMO and GLI are activated through other signaling pathways such as PKA, GTPase, PI3K/mTOR or Rho to enable target gene expression. PKA phosphorylates the C-terminus of SMO at three sites. PI3K could activate the signaling through AKT, mTOR and turn on gene expression. PI3K could interact with RhoA and Rac, which could have effect on the cytoskeleton. PLCγ could act on Ca²⁺ flux. Therefore, noncanonical HH signaling pathway can regulate cytoskeleton, cell migration, angiogenesis and Ca²⁺ oscillation.

Figure 3

SMO in cancer. Major Hedgehog signaling pathway molecules, HH ligands, Patched, SMO and GLI, are labeled in color. SMO inhibitors include vismodegib (GDC-0449), cyclopamine, TAK-441, etc. Molecules (MMP2, Rho, FoxF1, Bcl2, NFKB, etc.) interact with Hedgehog molecules; the direct interactions between molecules are shown with solid lines and the indirect relationships between molecules are shown with dotted lines. The figure was plotted using Ingenuity Pathway Analysis software.