Kakimoto Miku, Yamamoto Hideya, Tanaka Arowu R
Laboratory of Physiology and Morphology, Department of Life Sciences, School of Pharmacy, Yasuda Women's University, 6-13-1 Yasuhigashi, Asaminami Ward, Hiroshima City, Hiroshima, 731-0153, Japan.
Biochem Biophys Rep. 2020 Mar 27;22:100754. doi: 10.1016/j.bbrep.2020.100754. eCollection 2020 Jul.
The oxysterol 25-hydroxycholesterol (25-HC) has diverse physiological activities, including the ability to inhibit anchorage-independent growth of colorectal cancer cells. Here, we found that a polyamine synthesis inhibitor, DFMO, prevented 25-HC-induced apoptosis in non-anchored colorectal cancer DLD-1 cells. Additionally, we found that the spermine synthesis inhibitor APCHA also inhibited 25-HC-induced apoptosis in DLD-1 spheroids. Inhibiting the maturation of SREBP2, a critical regulator of cholesterol synthesis, reversed the effects of APCHA. SREBP2 knockdown also abolished the ability of APCHA to counteract 25-HC activity. Furthermore, APCHA induced SREBP2 maturation and upregulated its transcriptional activity, indicating that altered polyamine metabolism can increase SREBP2 activity and block 25-HC-induced apoptosis in spheroids. These results suggest that crosstalk between polyamine metabolism and cholesterol synthetic pathways via SREBP2 governs the proliferative and malignant properties of colorectal cancer cells.
氧化甾醇25-羟基胆固醇（25-HC）具有多种生理活性，包括抑制结肠癌细胞非锚定依赖性生长的能力。在此，我们发现一种多胺合成抑制剂DFMO可预防25-HC诱导的非锚定结肠癌细胞系DLD-1细胞凋亡。此外，我们发现精胺合成抑制剂APCHA也能抑制25-HC诱导的DLD-1球体凋亡。抑制胆固醇合成的关键调节因子SREBP2的成熟可逆转APCHA的作用。敲低SREBP2也消除了APCHA抵消25-HC活性的能力。此外，APCHA诱导SREBP2成熟并上调其转录活性，表明多胺代谢改变可增加SREBP2活性并阻断球体中25-HC诱导的凋亡。这些结果表明，通过SREBP2的多胺代谢与胆固醇合成途径之间的相互作用决定了结肠癌细胞的增殖和恶性特性。
