Diet Therapy Abates Mutant Apc and KRas Effects by Reshaping Plasma Membrane Cholesterol Nanodomains

Authors

Eunjoo Kim
Alfredo Erazo-Oliveras
Mónica Muñoz-Vega
Natividad R Fuentes
Michael L Salinas
Miranda J George
Roger S Zoh
Martha E Hensel
Bhimanagouda S Patil
Ivan Ivanov
Nancy D Turner
Robert S Chapkin

Language

English

Publication Date

2-4-2025

Journal

Biophysical Journal

DOI

10.1016/j.bpj.2024.12.020

PMID

39709523

PMCID

PMC11866957

PubMedCentral® Posted Date

12-20-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Cholesterol-enriched plasma membrane domains are known to serve as signaling platforms in a diverse array of cellular processes. However, the link between cholesterol homeostasis and mutant APC-KRas-associated colorectal tumorigenesis remains to be established. Thus, we investigated the impact of Apc-Kras on 1) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering, 2) colonocyte cell proliferation, and 3) whether these effects are modulated by select membrane active dietaries (MADs). We observed that oncogenic APC-KRas increased membrane order by perturbing cholesterol homeostasis when cell proliferation is upregulated, in part by altering the expression of genes associated with cholesterol influx, export and de novo synthesis in mouse colorectal cancer (CRC) models and CRC patients. In addition, oncogene-induced loss of cholesterol homeostasis altered Fzd7, LRP6, and KRas cluster structure/organization. Notably, we show that the combination of chemoprotective MADs, i.e., n-3 PUFAs and curcumin, reduced colonic membrane free cholesterol, order, receptor cluster size, cell proliferation, and the number of dysplastic foci in mutant APC-KRas models. This work highlights the dynamic shaping of plasma membrane organization during colon tumorigenesis and the utility of membrane-targeted cancer therapy.

Keywords

Cholesterol, Animals, Mice, Humans, Proto-Oncogene Proteins p21(ras), Cell Membrane, Adenomatous Polyposis Coli Protein, Mutation, Cell Proliferation, Colorectal Neoplasms, Diet, Membrane Microdomains, Homeostasis

Published Open-Access

yes

Recommended Citation

Kim, Eunjoo; Erazo-Oliveras, Alfredo; Muñoz-Vega, Mónica; et al., "Diet Therapy Abates Mutant Apc and KRas Effects by Reshaping Plasma Membrane Cholesterol Nanodomains" (2025). Faculty, Staff and Student Publications. 5645.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5645