Kaempferol Inhibits MMP-1-Mediated Migration and Invasion in Gemcitabine-Resistant Pancreatic Cancer Cells

Background: Pancreatic cancer (PaCa) has an extremely poor prognosis. This malignancy rapidly acquires resistance to gemcitabine (GEM), a key chemotherapeutic agent, yet the mechanisms underlying this resistance remain incompletely understood. We previously established GEM-resistant (GEM-R) PaCa cell lines and found that these cells exhibit constitutively increased levels of matrix metalloproteinase-1 (MMP-1), which contributes to the invasion and metastasis of PaCa. Kaempferol, a naturally occurring flavonoid found in many plant species, has been shown to exhibit antitumor effects across a range of cancers. Methods/Results: This study demonstrated that non-cytotoxic concentrations of kaempferol significantly decrease MMP-1 protein expression in GEM-R PaCa and suppress their migration and invasion capacities. Western blot analysis demonstrated that MMP-1 protein levels were upregulated in GEM-R PaCa cells and decreased upon kaempferol exposure. In Transwell migration/invasion and wound healing assays, GEM-R PaCa cell lines exhibited enhanced migration and invasion capacities compared with GEM-S cells, whereas kaempferol treatment suppressed these properties, similar to the effects observed by MMP-1 knockdown or treatment with the MMP inhibitor batimastat. Furthermore, kaempferol treatment reduced phosphorylated Akt expression and NF-κB p65 activity. Conclusions: These findings indicate that kaempferol suppresses the migratory and invasive abilities of PaCa cells by downregulating MMP-1 through negative regulation of the Akt and NF-κB signaling cascades, while kaempferol holds promise as a treatment strategy for GEM-R PaCa.