Diet therapy abates mutant APC and KRas effects by reshaping plasma membrane cholesterol nanodomains

Eunjoo Kim; Alfredo Erazo-Oliveras; Mónica Munoz-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

doi:10.1016/j.bpj.2024.12.020

Diet therapy abates mutant APC and KRas effects by reshaping plasma membrane cholesterol nanodomains

Biophys J. 2024 Dec 20:S0006-3495(24)04101-8. doi: 10.1016/j.bpj.2024.12.020. Online ahead of print.

Authors

Affiliations

¹ Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX 77843, USA,; Department of Molecular and Cellular Medicine, Texas A&M University, TX 77843, USA.
² Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX 77843, USA,; Department of Nutrition, Texas A&M University, College Station, TX 77843, USA,; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX 77843, USA.
³ Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77054.
⁴ Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX 77843, USA.
⁵ Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN 47405.
⁶ Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, University of Texas, Bastrop, TX 78602.
⁷ Vegetable and Fruit Improvement Center, Department of Horticultural Science, Texas A&M University, College Station, TX 77845.
⁸ Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX 77843, USA,; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843.
⁹ Department of Nutrition, Texas A&M University, College Station, TX 77843, USA.
¹⁰ Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, TX 77843, USA,; Department of Nutrition, Texas A&M University, College Station, TX 77843, USA,; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX 77843, USA,. Electronic address: [email protected].

PMID: 39709523
DOI: 10.1016/j.bpj.2024.12.020

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 (i) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering, (ii) colonocyte cell proliferation, and (iii) 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. Additionally, oncogene-induced loss of cholesterol homeostasis altered Fzd7, LRP6 and KRas cluster structure/organization. Notably, we show that the combination of chemo-protective 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.