Pentoxifylline Inhibits TNF-alpha/TGF-beta 1-Induced Epithelial-Mesenchymal Transition via Suppressing the NF-kappa B Pathway and SERPINE1 Expression in CaSki Cells

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-alpha) and Transforming growth factor-beta (TGF-beta 1) activate transcriptional factors such as STAT3, Snail, Smad, and the Nuclear Factor kappa light-chain-enhancer of activated beta cells (NF-kappa B), 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-kappa B 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-alpha 10 ng/mL and TGF-beta 1 alone or in combination for 5 days. Our results revealed that TNF-alpha and TGF-beta 1 induced N-cadherin and Vimentin, confirming the induction of EMT. Furthermore, the combination of cytokines synergized the expression of mesenchymal proteins, enhanced I kappa B-alpha and p65 phosphorylation, and upregulated Serpin family E member 1 (SERPINE1) mRNA. PTX pretreatment prior to the addition of TNF-alpha and TGF-beta 1 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 I kappa B-alpha and p65 and significantly decreased SERPINE1 expression, cell proliferation, migration, and invasion. In conclusion, PTX may counteract EMT in cervical cancer cells by decreasing the NF-kappa B and SERPINE1.

Automated summary

Cervical cancer is a common and deadly type of female cancer. Inflammation can lead to tumor metastasis and EMT. The anti-inflammatory compound PTX may disrupt EMT and reduce cell migration and invasion.