Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia P.O. Box 5110566, Chile.
Instituto de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia P.O. Box 5110566, Chile.
Biomolecules. 2023 Sep 12;13(9):1383. doi: 10.3390/biom13091383.
Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin's primary action mechanism, COX-independent ways are associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) is related to the increase in spermidine/spermine-N-acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells; however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-γ on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-γ with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.
吲哚美辛是一种非选择性的 NSAID，用于治疗疼痛和炎症。虽然环氧化酶 (COX) 抑制被认为是吲哚美辛的主要作用机制，但 COX 非依赖性途径与癌症的有益效应有关。在结肠癌细胞中，过氧化物酶体增殖物激活受体-γ (PPAR-γ) 的激活与多胺降解的关键酶 spermidine/spermine-N-acetyltransferase-1 (SSAT-1) 的增加有关，并且与细胞周期停滞有关。吲哚美辛增加肺癌细胞中的 SSAT-1 水平；然而，依赖于 SSAT-1 增加的机制尚不清楚。因此，我们研究了 PPAR-γ 对两种肺癌细胞系 H1299 和 A549 中 SSAT-1 表达的影响。我们发现，用 GW9662 抑制 PPAR-γ 并不能逆转吲哚美辛诱导的 SSAT-1 增加。由于 SSAT-1 的 mRNA 受到核仁蛋白核仁素的翻译前滞留步骤的影响，我们探索了吲哚美辛与 SSAT-1 的上游翻译调节剂之间的关系。我们发现，吲哚美辛降低核仁素水平和细胞周期蛋白依赖性激酶 1 (CDK1) 水平，CDK1 在有丝分裂中使核仁素磷酸化。核仁素的过表达部分逆转了吲哚美辛对细胞活力和 SSAT-1 水平的影响。另一方面，已知在有丝分裂期间使核仁素磷酸化的酪蛋白激酶不被吲哚美辛修饰。SSAT-1 通过乙酰化多胺发挥其抗增殖作用，该过程被多胺氧化酶 (PAOX) 逆转。最近，甲氯噻嗪被描述为最特异的 PAOX 抑制剂。因此，我们研究了甲氯噻嗪是否可以增强吲哚美辛的作用。我们发现，当联合使用时，吲哚美辛和甲氯噻嗪在体外对非小细胞肺癌细胞具有协同作用。这些结果表明，吲哚美辛通过降低 CDK1-核仁素调节轴来增加 SSAT-1 水平，而用甲氯噻嗪抑制 PAOX 可以提高吲哚美辛的抗增殖作用。
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