Doctoral Program in Biomedical Sciences Orientation Immunology, University Center for Health Science (CUCS), University of Guadalajara (UdeG), 44340 Guadalajara, Jalisco, Mexico.
Immunology Division, Biomedical Research Center West (CIBO), Mexican Social Security Institute, 44340 Guadalajara, Jalisco, Mexico.
Int J Mol Sci. 2023 Jun 24;24(13):10592. doi: 10.3390/ijms241310592.
Cervical cancer (CC) is one of the most common and deadly types of female cancer worldwide. Late diagnosis in CC increases the risk of tumor cells spreading to distant organs (metastasis). The epithelial-mesenchymal transition (EMT) is a fundamental process of cancer metastasis. Inflammation can lead to tumor progression, EMT induction, and metastasis. The inflammatory microenvironment is a potent inducer of EMT; inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Transforming growth factor-beta (TGF-β1) activate transcriptional factors such as STAT3, Snail, Smad, and the Nuclear Factor kappa light-chain-enhancer of activated beta cells (NF-κΒ), which drive EMT. Anti-inflammatory compounds may be an option in the disruption of EMT. PenToXifylline (PTX) possesses potent anti-inflammatory effects by inhibiting NF-κB activity. In addition, PTX exerts an anti-fibrotic effect by decreasing Smad2/3/4. We hypothesize that PTX could exert anti-EMT effects. CaSki human cervical tumor cells were exposed to TNF-α 10 ng/mL and TGF-β1 alone or in combination for 5 days. Our results revealed that TNF-α and TGF-β1 induced N-cadherin and Vimentin, confirming the induction of EMT. Furthermore, the combination of cytokines synergized the expression of mesenchymal proteins, enhanced IκBα and p65 phosphorylation, and upregulated Serpin family E member 1 () mRNA. PTX pretreatment prior to the addition of TNF-α and TGF-β1 significantly reduced N-cadherin and Vimentin levels. To our knowledge, this is the first time that this effect of PTX has been reported. Additionally, PTX reduced the phosphorylation of IκB-α and p65 and significantly decreased expression, cell proliferation, migration, and invasion. In conclusion, PTX may counteract EMT in cervical cancer cells by decreasing the NF-κB and .
宫颈癌（CC）是全球最常见和最致命的女性癌症之一。CC 的晚期诊断会增加肿瘤细胞扩散到远处器官（转移）的风险。上皮-间充质转化（EMT）是癌症转移的基本过程。炎症可导致肿瘤进展、EMT 诱导和转移。炎症微环境是 EMT 的有力诱导剂；炎症细胞因子如肿瘤坏死因子-α（TNF-α）和转化生长因子-β1（TGF-β1）激活转录因子如 STAT3、Snail、Smad 和核因子 kappa 轻链增强子的 B 细胞（NF-κB），驱动 EMT。抗炎化合物可能是破坏 EMT 的一种选择。Pentoxifylline（PTX）通过抑制 NF-κB 活性具有强大的抗炎作用。此外，PTX 通过降低 Smad2/3/4 发挥抗纤维化作用。我们假设 PTX 可能发挥抗 EMT 作用。CaSki 人宫颈肿瘤细胞暴露于 TNF-α 10ng/mL 和 TGF-β1 单独或联合培养 5 天。我们的结果表明，TNF-α 和 TGF-β1 诱导了 N-钙粘蛋白和波形蛋白，证实了 EMT 的诱导。此外，细胞因子的组合协同增强了间充质蛋白的表达，增强了 IκBα 和 p65 的磷酸化，并上调了丝氨酸蛋白酶家族 E 成员 1（）mRNA。PTX 在添加 TNF-α 和 TGF-β1 之前进行预处理可显著降低 N-钙粘蛋白和波形蛋白水平。据我们所知，这是首次报道 PTX 的这种作用。此外，PTX 降低了 IκB-α 和 p65 的磷酸化，并显著降低了 表达、细胞增殖、迁移和侵袭。总之，PTX 可能通过降低 NF-κB 和 来抵抗宫颈癌细胞中的 EMT。
