Frizzled7 as an emerging target for cancer therapy

Abstract

Wnt proteins are secreted glycoproteins that bind to the N-terminal extra-cellular cysteine-rich domain of the Frizzled (Fzd) receptor family. The Fzd receptors can respond to Wnt proteins in the presence of Wnt co-receptors to activate the canonical and non-canonical Wnt pathways. Recent studies indicated that, among the Fzd family, Fzd7 is the Wnt receptor most commonly upregulated in a variety of cancers including colorectal cancer, hepatocellular carcinoma and triple negative breast cancer. Fzd7 plays an important role in stem cell biology and cancer development and progression. In addition, it has been demonstrated that siRNA knockdown of Fzd7, the anti-Fzd7 antibody or the extracellular peptide of Fzd7 (soluble Fzd7 peptide) displayed anti-cancer activity in vitro and in vivo mainly due to the inhibition of the canonical Wnt signaling pathway. Furthermore, pharmacological inhibition of Fzd7 by small interfering peptides or a small molecule inhibitor suppressed β-catenin-dependent tumor cell growth. Therefore, targeted inhibition of Fzd7 represents a rational and promising new approach for cancer therapy.

Fig. 1

The canonical Wnt/β-catenin and non-canonical Wnt signaling pathways. In the Wnt/β-catenin pathway, Wnt ligands form a ternary complex with Fzd and LRP5/6, which disrupts the Axin, CK1, GSK3β, and β-catenin complex via the activation of Dvl. Subsequently, cytoplasmic β-catenin stability increases which results in the formation of the β-catenin/TCF transcriptional complex and the ensuing expression of respective target genes. The Wnt/Ca2+ pathway is activated via the interaction of Wnt with Fzd and the Ror2 receptors. This interaction recruits Dvl to the plasma membrane where it interacts with Fzd and G-proteins to increase intracellular Ca2+ levels, which activate CamkII, PKC, and NFAK. Activation of these three kinases results in the inhibition of Wnt/β-catenin signaling, the induction of tissue separation, and the regulation of ventral fate, respectively. In the Wnt/PCP pathway, Wnt interacts with Fzd and Ror2 and activates Dvl. Dvl in turn activates Rac1/RhoA, which activate JNK and ROCK2, respectively. JNK and ROCK2 are involved in cytoskeletal remodeling.

Fig. 2

Targeting Fzd7 in cancer. Based on the current literature, several methods have been designed to antagonize Wnt/β-catenin signaling by directly or indirectly targeting the Fzd7 receptor. For example, soluble Fzd7 peptide (sFzd7) binds to and inhibits the ability of Wnt proteins to interact with the CRD of Fzd7. The anti-Fzd7 antibody (Fzd7 Ab) blocks the ability of Wnt proteins to interact with Fzd7. Small molecule inhibitor FJ9 and small interfering peptides (RHPDs) disrupt the interaction of the C-terminal tail of Fzd7 with the PDZ domain of Dvl.