25-羟胆固醇通过激活结直肠癌细胞球中的 ROCK/LIMK/丝切蛋白轴诱导细胞死亡。
25-hydroxycholesterol-induced cell death via activation of ROCK/LIMK/cofilin axis in colorectal cancer cell spheroids.
机构信息
Faculty of Pharmacy, Yasuda Women's University, 6-13-1 Yasuhigashi, Asaminami Ward, Hiroshima City, Hiroshima 731-0153, Japan.
Faculty of Pharmacy, Yasuda Women's University, 6-13-1 Yasuhigashi, Asaminami Ward, Hiroshima City, Hiroshima 731-0153, Japan.
出版信息
J Steroid Biochem Mol Biol. 2022 Feb;216:106037. doi: 10.1016/j.jsbmb.2021.106037. Epub 2021 Nov 30.
25-Hydroxycholesterol (25OHC) induces anchorage-dependent programmed cell death, or anoikis, in colorectal cancer cells but the mechanism is not fully understood. Here, we found that 25OHC induced cofilin phosphorylation and promoted rearrangement of the actin cytoskeleton in spheroids of the colorectal cancer cell lines, DLD1 and HT29/WiDr. Cell death induced by 25OHC was inhibited by the actin polymerization inhibitor, cytochalasin D, and BMS-3, an inhibitor of LIMK, which phosphorylates and inactivates cofilin. In addition, we showed that cofilin phosphorylation induced by 25OHC was associated with caspase-3 activation, which can activate ROCK. Rho GTPase was directly activated by 25OHC. These results indicate that 25OHC affects actin dynamics through activation of the Rho/ROCK/LIMK/cofilin axis, eventuating in the cell death of colorectal cancer cell spheroids.
25-羟胆固醇（25OHC）可诱导结直肠癌细胞发生锚定依赖性程序性细胞死亡，即细胞凋亡，但具体机制尚不完全清楚。本研究发现，25OHC 可诱导结直肠癌细胞系 DLD1 和 HT29/WiDr 球体中原肌球蛋白磷酸化，并促进细胞骨架肌动蛋白的重排。细胞骨架聚合抑制剂细胞松弛素 D 和 LIMK 抑制剂 BMS-3 可抑制 25OHC 诱导的细胞死亡，LIMK 可磷酸化并使原肌球蛋白失活。此外，我们还发现 25OHC 诱导的原肌球蛋白磷酸化与 caspase-3 激活有关，caspase-3 可激活 ROCK。25OHC 可直接激活 Rho GTPase。这些结果表明，25OHC 通过激活 Rho/ROCK/LIMK/原肌球蛋白轴影响肌动蛋白动力学，导致结直肠癌细胞球体死亡。
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