Wnt antagonist as therapeutic targets in ovarian cancer

Abstract

Ovarian cancer is a fatal malignancy in women with a low survival rate that demands new therapeutic paradigms. Cancer cells acquire various exclusive alterations to proliferate, invade, metastasize, and escape cell death, acting independently of growth-inducing or growth-inhibiting signals. The nature of cellular signaling in tumorigenesis is interwoven. Wnt signaling is an evolutionarily conserved signaling cascade that has been shown to regulate ovarian cancer pathogenesis. The molecular mechanism of Wnt signaling underlying the development of ovarian cancer, drug resistance, and relapse is not completely understood. Extracellularly secreted Wnt signaling inhibitors are crucial regulators of ovarian cancer tumorigenesis and malignant properties of cancer stem cells. Wnt inhibitors arbitrated modifications affecting Wnt pathway proteins on the cell membranes, in the cytoplasm, and in the nucleus have been shown to span essential contributions in the initiation, progression, and chemoresistance of ovarian cancer. Although many extrinsic inhibitors developed targeting the downstream components of the Wnt signaling pathway, investigating the molecular mechanisms of endogenous secreted inhibitors might substantiate prognostic or therapeutic biomarkers development. Given the importance of Wnt signaling in ovarian cancer, more systematic studies combined with clinical studies are requisite to probe the precise mechanistic interactions of Wnt antagonists in ovarian cancer. This review outlines the latest progress on the Wnt antagonists and ovarian cancer-specific regulators such as micro-RNAs, small molecules, and drugs regulating these Wnt antagonists in ovarian tumourigenesis.

Keywords: Biomarker; Cancer stem cell; Novel targets; Ovarian cancer; Wnt antagonists; Wnt signaling.

Fig. 1

a. Illustration of tumor formation in the ovary gives rise to all types of cells with aberrant mutations and stemness characteristics. The tumor-initiating cells detach from the primary tumor cells and undergo EMT transition. These cancer stem cells (CSC) spread through invasion, migration, and metastasize to different organs. b.Overview of Wnt/β-catenin dependent and Wnt/β-catenin independent pathway. Canonical Wnt pathway is activated by binding Wnt ligand to Frizzled (Fzd) receptor, and LRP5/6 co-receptor leads to the phosphorylation of CK1α and GSK3β, which recruits Disheveled (Dvl) protein. The activated Dvl protein inactivates the β-catenin destruction complex. It stabilizes β-catenin accumulation in the cytoplasm, which then translocates into the nucleus leading to the transcription of various β-catenin target genes. In inhibited state (i.e., absence of Wnt ligands), GSK3β phosphorylates β-catenin in the cytoplasm and undergoes β-TrCp mediated ubiquitination and proteasomal degradation. In the absence of nuclear β-catenin, the transcription of various β-catenin target genes is repressed. In the non-canonical pathway (Wnt/PCP), Wnt proteins bind the ROR-Fzd receptor and recruit the Dvl protein. Dvl binds GTPase Rho and activates GTPase Rac1/Rho triggered Rho kinase (ROCK) and JNK proteins which control transcriptional reactions. Wnt/Ca2+ signaling is stimulated by G-protein-initiated phospholipase C (PLC) forwarding to intracellular calcium levels and upregulating Ca2+ dependent cytoskeletal reactions.

Fig. 2. Schematic representation of endogenously expressed extracellular Wnt antagonist interfering Wnt signaling pathway.

Fig. 3. The visual presentation gives an overview of miRNAs and small molecules which bind Wnt antagonist to promote/repress the Wnt signaling pathway.