The dietary terpene lupeol targets colorectal cancer cells with constitutively active Wnt/β-catenin signaling.

Abstract

SCOPE:

Aberrant activation of the Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin signaling pathway is the most common modification, and often considered, a hallmark of colorectal cancer (CRC). Typically in this pathway the β-catenin translocates from the cytoplasm to the nucleus, where it functions as a transcription regulator of several genes that support tumor formation and progression. Thus, any agent that could attenuate the translocation of β-catenin could be extremely valuable against CRC, especially the tumors that exhibit constitutively active Wnt/β-catenin signaling.

METHODS AND RESULTS:

Using human CRC cells that exhibit differential expression of Wnt/β-catenin signaling, we demonstrate that treatment of CRC cells with dietary triterpene lupeol results in a dose-dependent (i) decrease in cell viability, (ii) induction of apoptosis, (iii) decrease in colonogenic potential, (iv) decrease in β-catenin transcriptional activity, and (v) decrease in the expression of Wnt target genes. Most importantly lupeol was observed to inhibit the translocation of β-catenin from the cytoplasm to the nucleus. Importantly, all these effects of lupeol were restricted to cells that harbor constitutively active Wnt/β-catenin signaling while negligible effects were observed in cells that lack constitutively active Wnt/β-catenin signaling. Further, we also demonstrate that inhibition of Wnt signaling in cells with constitutive active Wnt/β-catenin results in loss of lupeol efficacy while inducing Wnt signaling sensitizes the cells to inhibitory effects of lupeol.

CONCLUSION:

In summary, our data strongly advocate the efficacy of lupeol against CRC cells that exhibit constitutively active Wnt/β-catenin signaling.

• Authors: Rohinton S Tarapore, Imtiaz A Siddiqui, Vaqar M Adhami, Vladimir S Spiegelman, Hasan Mukhtar
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 57 Issue 11 Pg. 1950-8 (Nov 2013) ISSN: 1613-4133 [Electronic] Germany
• PMID: 23836602 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• CTNNB1 protein, human
• Pentacyclic Triterpenes
• beta Catenin
• lupeol

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (metabolism, pathology)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic
• Humans
• Pentacyclic Triterpenes (pharmacology)
• Phosphorylation
• Wnt Signaling Pathway (drug effects)
• beta Catenin (genetics, metabolism)