Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC‐3 and Ca9‐22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)‐2 and MMP‐9 activities and expressions as well as epithelial‐mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal‐regulated kinases 1/2 (ERK1/2), but not c‐Jun N‐terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx‐suppressed transwell migration and MMP‐2/−9 activities in HSC‐3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells.

中文翻译：

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石榴提取物通过下调基质金属蛋白酶2/9和上皮间质转化抑制口腔癌细胞的迁移和侵袭

发现用于调节转移的候选药物对于抑制口腔癌恶性肿瘤具有重要意义。尽管大多数石榴提取物的应用旨在抗癌细胞增殖，但其抗转移作用尚不清楚，尤其是对口腔癌细胞。本研究的目的是评估口腔癌细胞迁​​移和侵袭两种主要转移特征的变化。此外，我们想探索石榴提取物 (POMx) 在低细胞毒性浓度下的分子作用机制。我们发现 POMx 的范围从 0 到 50 μg/mL，显示出对口腔癌细胞的低细胞毒性。在口腔癌 HSC-3 和 Ca9-22 细胞的情况下，POMx 抑制伤口愈合迁移、transwell 迁移和基质凝胶侵入。从机制上讲，POMx 下调基质金属蛋白酶 (MMP)-2 和 MMP-9 的活性和表达以及上皮间质转化 (EMT) 信号。POMx 上调细胞外信号调节激酶 1/2 (ERK1/2)，但不上调 c-Jun N 端激酶 (JNK) 和 p38 的表达。添加 ERK1/2 抑制剂 (PD98059) 可显着恢复 HSC-3 细胞中 POMx 抑制的跨孔迁移和 MMP-2/-9 活性。综上所述，这些发现建议进一步测试低细胞毒性浓度的 POMx 作为针对口腔癌细胞的潜在抗转移疗法。添加 ERK1/2 抑制剂 (PD98059) 可显着恢复 HSC-3 细胞中 POMx 抑制的跨孔迁移和 MMP-2/-9 活性。综上所述，这些发现建议进一步测试低细胞毒性浓度的 POMx 作为针对口腔癌细胞的潜在抗转移疗法。添加 ERK1/2 抑制剂 (PD98059) 可显着恢复 HSC-3 细胞中 POMx 抑制的跨孔迁移和 MMP-2/-9 活性。综上所述，这些发现建议进一步测试低细胞毒性浓度的 POMx 作为针对口腔癌细胞的潜在抗转移疗法。