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Published on: October 6, 2014
Diet therapy abates mutant APC and KRas effects by reshaping plasma membrane cholesterol nanodomains
Eunjoo Kim1, Alfredo Erazo-Oliveras2, Mónica Muñoz-Vega2
1Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas.
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.
Insights
Mutant APC-KRas disrupts colon cell cholesterol balance, increasing membrane order and promoting cancer. Certain dietary lipids and curcumin can reverse these effects, offering a potential therapy for colorectal cancer.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- Cholesterol-rich membrane domains act as signaling platforms.
- The relationship between cholesterol homeostasis and APC-KRas-driven colorectal cancer is unclear.
Purpose of the Study:
- Investigate Apc-Kras effects on colonocyte membrane cholesterol, order, and nanoclustering.
- Assess Apc-Kras impact on colonocyte proliferation.
- Determine if membrane-active dietaries (MADs) modulate these effects.
Main Methods:
- Utilized mouse colorectal cancer (CRC) models and CRC patient samples.
- Analyzed gene expression related to cholesterol metabolism.
- Examined Fzd7, LRP6, and KRas receptor organization.
- Assessed effects of n-3 PUFAs and curcumin.
Main Results:
- Oncogenic APC-KRas perturbs cholesterol homeostasis, increasing membrane order during heightened cell proliferation.
- Altered gene expression impacts cholesterol influx, efflux, and synthesis.
- Loss of cholesterol homeostasis affects Fzd7, LRP6, and KRas nanoclustering.
- Combined n-3 PUFAs and curcumin reduced cholesterol, membrane order, proliferation, and dysplasia in CRC models.
Conclusions:
- Colon tumorigenesis involves dynamic alterations in plasma membrane organization.
- Targeting membrane cholesterol homeostasis presents a viable therapeutic strategy for colorectal cancer.
- Dietary interventions with n-3 PUFAs and curcumin show promise in mitigating APC-KRas-driven colon cancer.
