Nutrients, Vol. 18, Pages 380: Kaempferol Inhibits MMP-1-Mediated Migration and Invasion in Gemcitabine-Resistant Pancreatic Cancer Cells
Nutrients doi: 10.3390/nu18030380
Authors:
Saburo Sugita
Yoichi Matsuo
Masaki Ishida
Yuriko Uehara
Yuki Eguchi
Yuki Denda
Keisuke Nonoyama
Hiromichi Murase
Tomokatsu Kato
Kenta Saito
Takafumi Sato
Yushi Yamakawa
Hiroyuki Sagawa
Ryo Ogawa
Hiroki Takahashi
Akira Mitsui
Shuji Takiguchi
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.
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. Read More