Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers.

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways.

Chemical-genetic screen identifies riluzole as an enhancer of Wnt/β-catenin signaling in melanoma.

To identify new protein and pharmacological regulators of Wnt/β-catenin signaling, we used a cell-based reporter assay to screen a collection of 1857 human-experienced compounds for their ability to enhance activation of the β-catenin reporter by a low concentration of WNT3A. This identified 44 unique compounds, including the FDA-approved drug riluzole, which is presently in clinical trials for treating melanoma. We found that treating melanoma cells with riluzole in vitro enhances the ability of WNT3A to regulate gene expression, to promote pigmentation, and to decrease cell proliferation.

Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain.

Wnt/beta-catenin signaling can influence the proliferation and differentiation of progenitor populations in the hippocampus and subventricular zone, known germinal centers in the adult mouse brain. It is not known whether beta-catenin signaling occurs in quiescent glial progenitors in cortex or spinal cord, nor is it known whether beta-catenin is involved in the activation of glial progenitor populations after injury. Using a beta-catenin reporter mouse (BATGAL mouse), we show that beta-catenin signaling occurs in NG2 chondroitin sulfate proteoglycan+ (NG2) progenitors in the cortex, in subcallosal zone (SCZ) progenitors, and in subependymal cells surrounding the central canal.

Wnt signaling: it gets more humorous with age.

In addition to its myriad of contributions in development, disease and regeneration, recent research implicates the Wnt/beta-catenin signaling cascade in yet another biological process - aging. The latest role of Wnt uncovers new complexities and opportunities for modulating the Wnt/beta-catenin pathway in regenerative medicine.

Identification of midkine as a mediator for intercellular transfer of drug resistance.

Resistance to cytotoxic agents is a major limitation for their clinical use to treat human cancers. Tumors become resistant to chemotherapy when a subset of cells undergoes molecular changes leading to overexpression of drug transport proteins, alterations in drug-target interactions or reduced ability to commit apoptosis. However, such changes may not be sufficient to explain why both resistant and nonresistant cells survive drug's action in tumors that ultimately become drug resistant.