AdipoRon Attenuates Wnt Signaling by Reducing Cholesterol-Dependent Plasma Membrane Rigidity
AdipoRon Attenuates Wnt Signaling by Reducing Cholesterol-Dependent Plasma Membrane Rigidity
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DOI：
10.1016/j.bpj.2019.09.009
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发表时间：
2020-02-25
影响因子：
3.4
通讯作者：
Chapkin, Robert S.
中科院分区：
文献类型：
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作者：
Salinas, Michael L.;Fuentes, Natividad R.;Chapkin, Robert S.
成人和青少年肥胖症患病率的增加及其相关的结直肠癌风险加强了阐明肥胖个体促进结肠癌发生的潜在机制的迫切需要。脂联素是一种脂肪组织衍生的脂肪因子，其水平在肥胖时降低。流行病学和临床前数据表明，脂联素抑制结肠肿瘤的发生。我们之前已经证明脂联素和AdipoRon（一种小分子脂联素受体激动剂）通过减少小鼠结肠类器官中Lgr5（+）干细胞的数量来抑制结肠癌的风险。然而，脂联素信号通路降低结肠癌风险的机制仍有待研究。在这里，我们假设脂联素信号通过调节质膜（PM）的生物物理特性来支持结肠干细胞的维持。具体而言，我们分别通过LEF荧光素酶报告试验和结肠类器官增殖研究了AdipoRon激活脂联素受体对wnt驱动信号衰减和细胞增殖相关的生物物理扰动的影响。使用物理化学敏感染料Di-4-ANEPPDHQ和C-laurdan，我们证明AdipoRon降低了结肠细胞PM的刚性。膜硬度的降低与PM游离胆固醇水平的降低和溶酶体中游离胆固醇的细胞内积累有关。这些结果表明，脂联素信号传导在调节细胞胆固醇稳态、PM生物物理特性和wnt驱动信号传导中发挥作用。这些发现值得注意，因为它们可能在一定程度上解释了肥胖是如何导致结肠癌进展的。
The increasing prevalence of adult and adolescent obesity and its associated risk of colorectal cancer reinforces the urgent need to elucidate the underlying mechanisms contributing to the promotion of colon cancer in obese individuals. Adiponectin is an adipose tissue-derived adipokine, whose levels are reduced during obesity. Both epidemiological and preclinical data indicate that adiponectin suppresses colon tumorigenesis. We have previously demonstrated that both adiponectin and AdipoRon, a small-molecule adiponectin receptor agonist, suppress colon cancer risk in part by reducing the number of Lgr5(+) stem cells in mouse colonic organoids. However, the mechanism by which the adiponectin signaling pathway attenuates colon cancer risk remains to be addressed. Here, we have hypothesized that adiponectin signaling supports colonic stem cell maintenance through modulation of the biophysical properties of the plasma membrane (PM). Specifically, we investigated the effects of adiponectin receptor activation by AdipoRon on the biophysical perturbations linked to the attenuation of Wnt-driven signaling and cell proliferation as determined by LEF luciferase reporter assay and colonic organoid proliferation, respectively. Using physicochemical sensitive dyes, Di-4-ANEPPDHQ and C-laurdan, we demonstrated that AdipoRon decreased the rigidity of the colonic cell PM. The decrease in membrane rigidity was associated with a reduction in PM free cholesterol levels and the intracellular accumulation of free cholesterol in lysosomes. These results suggest that adiponectin signaling plays a role in modulating cellular cholesterol homeostasis, PM biophysical properties, and Wnt-driven signaling. These findings are noteworthy because they may in part explain how obesity drives colon cancer progression.