Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy.
Systems Biology Group, Rome, Italy.
J Pineal Res. 2018 May;64(4):e12467. doi: 10.1111/jpi.12467. Epub 2018 Mar 8.
Through activation of the ERK pathway, nicotine, in both normal MCF-10A and low-malignant breast cancer cells (MCF7), promotes increased motility and invasiveness. Melatonin antagonizes both these effects by inhibiting almost completely ERK phosphorylation. As melatonin has no effect on nonstimulated cells, it is likely that melatonin can counteract ERK activation only downstream of nicotine-induced activation. This finding suggests that melatonin hampers ERK phosphorylation presumably by targeting a still unknown intermediate factor that connects nicotine stimulation to ERK phosphorylation. Furthermore, downstream of ERK activation, melatonin significantly reduces fascin and calpain activation while restoring normal vinculin levels. Melatonin also counteracts nicotine effects by reshaping the overall cytoskeleton architecture and abolishing invasive membrane protrusion. In addition, melatonin decreases nicotine-dependent ROCK1/ROCK2 activation, thus further inhibiting cell contractility and motility. Melatonin actions are most likely attributable to ERK inhibition, although melatonin could display other ERK-independent effects, namely through a direct modulation of additional molecular and structural factors, including coronin, cofilin, and cytoskeleton components.
通过激活 ERK 通路，尼古丁在正常 MCF-10A 和低恶性乳腺癌细胞（MCF7）中均促进了运动性和侵袭性的增加。褪黑素通过几乎完全抑制 ERK 磷酸化拮抗了这两种作用。由于褪黑素对未受刺激的细胞没有影响，因此褪黑素可能仅在尼古丁诱导的激活下游才能够拮抗 ERK 激活。这一发现表明，褪黑素通过靶向连接尼古丁刺激和 ERK 磷酸化的未知中间因子来抑制 ERK 磷酸化。此外，在 ERK 激活的下游，褪黑素显著降低了 fascin 和 calpain 的激活，同时恢复了正常的 vinculin 水平。褪黑素还通过重塑整个细胞骨架结构并消除侵袭性膜突来对抗尼古丁的作用。此外，褪黑素降低了尼古丁依赖性 ROCK1/ROCK2 的激活，从而进一步抑制了细胞收缩性和运动性。褪黑素的作用很可能归因于 ERK 抑制，尽管褪黑素可能通过直接调节其他分子和结构因素（包括 coronin、cofilin 和细胞骨架成分）发挥其他 ERK 非依赖性作用。
