Phenyllactic acid promotes cell migration and invasion in cervical cancer via IKK/NF-κB-mediated MMP-9 activation

Abstract

Background Persistent infection with high-risk human papillomavirus (hrHPV) is associated with cervical cancer development. This process involves the virus-encoded E6 and E7 oncoproteins, which are maintained and expressed during all malignant transformation stages. However, HPV alone is insufficient to drive tumor progression-related behaviors such as cervical cancer cell motility. In this study, we investigated the effect of phenyllactic acid (PLA), a phenolic acid phytochemical and biomarker for discriminating various cancers, on the metastatic potential of cervical cancer cells. Methods The effects of PLA on HPV16/18 E6/E7 expression, migratory and invasive behavior, and matrix metalloproteinases (MMPs) expression of cervical cancers cells were measured. Specific inhibitors were used to further investigate biological function and underlying mechanism of PLA modulated cell motility. Results PLA significantly promoted the migration and invasion of SiHa, HeLa, and C-33A cervical cancer cells as well as upregulated matrix metalloproteinase-9 (MMP-9) expression. Moreover, PLA treatment attenuated E6/E7 expression in SiHa and HeLa cells. Further molecular analysis showed that PLA activated the nuclear factor-kappa B (NF-κB) signaling pathway and increased the nuclear translocation of both IκBα and p65. Treating cervical cancer cells with an NF-κB inhibitor potently reversed PLA-induced migratory and invasive behavior, MMP-9 upregulation, and/or E6/E7 downregulation. The PLA-induced NF-κB activation and MMP-9 upregulation were mediated by IκB kinase-β (IKK-β) phosphorylation via PKC signals. The results suggested that SiHa, HeLa, and C-33A cells might undergo a similar process to enhance their motility in response to PLA, regardless of the HPV status. Conclusions Collectively, our study reveals a new biological function of PLA and elucidate the possible molecular role of PLA as a risk factor for triggering cervical cancer cell motility.

Altered Expressions of Matrix Metalloproteinases 2 and 9 in Cervical Carcinoma with high risk HPV-16 and HPV-18 in a South Indian Population: A Pilot Study

“…We also found a significant increase in gene expression of VEGF, MMP-2 and MMP-9. Similar results as been observed in a study by Li et al (17) . Another study demonstrated by Guo et al (23) where MMP-9 expression was associated with lymph node metastasis, suggested an invasive potential in early stages of ca cervix.…”

“…Despite widespread availability of HPV vaccines, Ca cervix is one of the major causes of cancerrelated death in women worldwide (1) . It has been proved that the enhanced activity of the MMPs, and VEGF by various analytes is strongly linked to a number of tumors (16)(17)(18)(19)(20) . Vascular endothelial growth factor is considered to be an important factor in blood vessel formation (angiogenesis), which is closely connected with tumor progression and metastasis (21) .…”

Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma

“…In keeping with our findings, other reports suggested that DL-3-phenyllactic acid, L-tryptophan, glycocholic acid and 1-methylnicotinamide have close relationships with the onset or progression of different cancers. [22][23][24][25][26][27][28][29] DL-3-phenyllactic acid was recognised as a potential biomarker for ovarian cancer, 23 oral squamous cell carcinoma 22 and cervical cancer. 25 DL-3-phenyllactic acid promotes cell migration and invasion in cervical cancer.…”

Effects of <i>Coriandrum sativum</i> on Migration and Invasion Abilities of Cancer Cells

“…Several studies showed that Erk 1/2 and NF-kB played an important role in metastasis through their effects on cell migration (31,32). Indeed, it was reported that MAPKs and IKK signaling pathways upregulated the expression of MMPs (33,34). Furthermore, it was demonstrated that berberine, one of the main substances of the plant Rhizoma coptidis, greatly reduced the phosphorylation of JNK, p38 and Erk 1/2, and decreased the protein levels of u-PA, MMP-2 and MMP-9 in SCC-4 cell (35).…”