Kim Eunjoo, Erazo-Oliveras Alfredo, Muñoz-Vega Mónica, Fuentes Natividad R, Salinas Michael L, George Miranda J, Zoh Roger S, Hensel Martha E, Patil Bhimanagouda S, Ivanov Ivan, Turner Nancy D, Chapkin Robert S
Program 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.
Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Nutrition, Texas A&M University, College Station, Texas; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, Texas.
Biophys J. 2025 Feb 4;124(3):508-527. doi: 10.1016/j.bpj.2024.12.020. Epub 2024 Dec 20.
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.
富含胆固醇的质膜结构域在多种细胞过程中作为信号平台发挥作用。然而，胆固醇稳态与突变型APC-KRas相关的结直肠癌发生之间的联系仍有待确定。因此，我们研究了Apc-Kras对以下方面的影响：1）结肠细胞质膜胆固醇稳态、有序性和受体纳米聚簇；2）结肠细胞增殖；3）这些效应是否受到特定膜活性饮食（MADs）的调节。我们观察到，在小鼠结直肠癌（CRC）模型和CRC患者中，当细胞增殖上调时，致癌性APC-KRas通过扰乱胆固醇稳态增加膜有序性，部分是通过改变与胆固醇内流、外流和从头合成相关的基因表达来实现的。此外，致癌基因诱导的胆固醇稳态丧失改变了Fzd7、LRP6和KRas的簇结构/组织。值得注意的是，我们发现化学保护性MADs（即n-3多不饱和脂肪酸和姜黄素）的组合降低了突变型APC-KRas模型中结肠膜游离胆固醇、有序性、受体簇大小、细胞增殖和发育异常病灶的数量。这项工作突出了结直肠癌发生过程中质膜组织的动态塑造以及膜靶向癌症治疗的效用。
