Abstract
The Wnt/β-catenin signaling pathway is known to play critical roles in a wide range of cellular processes: cell proliferation, differentiation, migration and embryonic development. Importantly, dysregulation of this pathway is tightly associated with pathogenesis in most human cancers. Therefore, the Wnt/β-catenin pathway has emerged as a promising target in anticancer drug screening programs. In the present study, we have isolated three previously unreported metabolites from an undescribed sponge, a species of Monanchora (Order Poecilosclerida, Family Crambidae), closely related to the northeastern Pacific species Monanchora pulchra, collected from deep waters off the Aleutian Islands of Alaska. Through an assortment of NMR, MS, ECD, computational chemical shifts calculation, and DP4, chemical structures of these metabolites have been characterized as spirocyclic ring-containing sesterterpenoid (1) and cholestane-type steroidal analogues (2 and 3). These compounds exhibited the inhibition of β-catenin response transcription (CRT) through the promotion of β-catenin degradation, which was in part implicated in the antiproliferative activity against two CRT-positive colon cancer cell lines.
Highlights
Colorectal cancer is the fourth most prevalent cancer and the third leading cause of cancer-related mortality worldwide
The molecular formula of 1 was deduced to be C27 H36 O6 based on High-resolution Electrospray Ionization mass (HRESIMS) data
The geometries of these conformers were optimized at B3LYP/6-31G(d) basis set in the polarizable continuum solvation model (PCM) with a dielectric constant representing MeOH
Summary
Colorectal cancer is the fourth most prevalent cancer and the third leading cause of cancer-related mortality worldwide. A multitude of research has shown that abnormal activation of the Wnt/β-catenin pathway frequently occurs in various cancer types (e.g., colorectal, leukemia, prostate and breast) [3]. We have reported that the flavonoid galangin effectively inhibits β-catenin response transcription (CRT) by promoting β-catenin degradation in colon cancer cell lines [11], and new. 4,9-friedodrimane-type sesquiterpenoids, isolated from a marine sponge, suppress β-catenin expression and exhibit cytotoxic activity in colon cancer cells [12]. A number of sterols have been elucidated from this genus [26,27] Based on these diverse findings, we report the investigation of an undescribed species of Monanchora, closely related to the Northeastern Pacific species, Monanchora pulchra [28], collected from deep waters off the Aleutian Islands of Alaska. The isolated compounds were evaluated for their inhibitory activity of β-catenin response transcription (CRT) and antiproliferative activity against CRT-positive colon cancer cells
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