A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis

Abstract

The Wnt/β-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/β-catenin signaling pathway is closely related to tumorigenesis. In order to identify potent small molecules to treat the over-activated Wnt signaling-mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15-oxospiramilactone (NC043) that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin D1 and Survivin, as well as decreases in the protein levels of Cdc25c and Cdc2. NC043 did not affect the cytosol-nuclear distribution and protein level of soluble β-catenin, but decreased β-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of β-catenin stability and may be a potential compound for treating colorectal cancer.

A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

“…In previous studies, high concentrations of S3 were found to induce apoptosis, through inhibition of the Wnt pathway [40] or upregulation of Bim [46]. However, at a low concentration, such as 2 µM, S3 does not induce apoptosis, indicating a completely different mechanism for the mitochondrial fusion induced by S3.…”

“…In these cells, small-fragmented mitochondria dispersed within the cell and the elongation of mitochondria was readily detectable. From the 300 compounds obtained, we identified 15-oxospiramilactone, a diterpenoid derivative (named S3 hereafter) [40], which could induce remarkable mitochondrial elongation in cells that lack Mfn1. Using a mitochondrial matrix-targeted DsRed protein, we monitored mitochondrial morphological changes at the singlecell level in real time ( Figure 1A).…”

Mitofusins: ubiquitylation promotes fusion

“…The anti-cancer properties of 15-oxospiramilactone, also named S3 or NC043, have been previously reported [10,11]. It inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis in a xenograft model [10]. Moreover, 15-oxospiramilactone increases Bim expression and apoptosis to inhibit tumor growth from Bax −/− /Bak −/− cells implanted in mice [11].…”

“…Therefore, this study potentiates 15-oxospiramilactone for therapeutical benefit. The anti-cancer properties of 15-oxospiramilactone, also named S3 or NC043, have been previously reported [10,11]. It inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis in a xenograft model [10].…”

Winning WNT: Race to Wnt signaling inhibitors

“…1). A number of inhibitors have been found that act at different steps in the Wnt/β-catenin signal transduction pathway (3,(7)(8)(9)(10)(11)(12)(13)(14)(15). However, because Wnt-receptor interaction can trigger both canonical and noncanonical intracellular pathways, interfering with membrane-adjacent events could conceivably have far-reaching effects.…”