Caffeine induces matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 down‐regulation in human leukemia U937 cells via Ca²⁺/ROS‐mediated suppression of ERK/c‐fos pathway and activation of p38 MAPK/c‐jun pathway

Abstract

Caffeine attenuated invasion of human leukemia U937 cells with characteristic of decreased protein expression and mRNA levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. Down-regulation of MMP-2 and MMP-9 in U937 cells was abrogated by abolishment of caffeine-elicited increase in intracellular Ca(2+) concentration and ROS generation. Pretreatment with BAPTA-AM (Ca(2+) chelator) and N-acetylcysteine (ROS scavenger) abolished caffeine-induced ERK inactivation and p38 MPAK activation. Moreover, caffeine treatment led to MAPK phosphatase-1 (MKP-1) down-regulation and protein phosphatase 2A catalytic subunit (PP2Ac) up-regulation, which were involved in cross-talk between p38 MAPK and ERK. Transfection of constitutively active MEK1 or pretreatment with SB202190 (p38 MAPK inhibitor) restored MMP-2 and MMP-9 protein expression in caffeine-treated cells. Caffeine treatment repressed ERK-mediated c-Fos phosphorylation but evoked p38 MAPK-mediated c-Jun phosphorylation. Knock-down of c-Fos and c-Jun by siRNA reflected that c-Fos counteracted the effect of c-Jun on MMP-2/MMP-9 down-regulation. Taken together, our data indicate that MMP-2/MMP-9 down-regulation in caffeine-treated U937 cells is elicited by Ca(2+)/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/c-Jun pathway.

Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma

“…MMP-2 and MMP-9 are important members of the MMP family, which and promote cancer-cell migration and invasion by degrading extracellular matrix components (2,(14)(15)(16)(17)). An increasing number of studies demonstrated that MMP-2 and MMP-9 have important roles in GBM angiogenesis and can be regulated by multiple pathways (23)(24)(25).…”

“…It has been demonstrated that MMP-2 and MMP-9 are mostly associated with migration and invasion in multiple tumor types (14)(15)(16). Further studies have shown that the expression of MMP-2 and MMP-9 in several cancer types is mediated by numerous signaling pathways, which include the hedgehog signaling pathway, the wnt/β-catenin pathway, the phosphoinositide-3 kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase (MAPK) pathway (10,17,18). It has been suggested that the hedgehog signaling pathway is cross-linked with other signaling pathways.…”

Caffeine Inhibits Migration in Glioma Cells through the ROCK-FAK Pathway

“…Although caffeine has been reported to reduce cell migration and invasion, the mechanism responsible for these effects remains unclear [7,17]. Caffeine alters IP3R and subsequently, intracellular calcium levels, which reduce migration and invasion in human glioma cells [7].…”

“…Caffeine alters IP3R and subsequently, intracellular calcium levels, which reduce migration and invasion in human glioma cells [7]. In non-glioma cells, caffeine decreases invasion of human leukemia U937 cells through the Ca 2+ /ROS-mediated suppression of ERK/c-fos and activation of p38 MAPK/ c-jun pathways [17]. Furthermore, caffeine inhibits the motility of extra-villous trophoblasts by blocking the mammalian target of rapamycin complex 2 and Akt [18].…”

Pro-Oxidant Natural Products as Anticancer Agents

“…glaucocalyx (Lamiaceae) [288] Guggulsterone Triterpenoid Commiphora mukul (Burseraceae) [289,290] Gypenosides Triterpenoid Gynostemma pentaphyllum (Cucurbitaceae) [291,292] Helenalin Sesquiterpenoid Arnica spp. (Asteraceae) [293] Linalool Monoterpenoid Coriandrum sativum (Apiaceae), widespread [294] ( [345][346][347] Camptothecin Quinoline Camptotheca acuminata (Nyssaceae) [7,348] Cepharanthine Isoquinoline Stephania cepharantha (Menispermaceae) [349,350] ( vate, which is an efficient scavenger of H 2 O 2 [75][76][77][78]. Second, glucose metabolism through the pentose phosphate pathway regenerates NADPH from NADP + in a reaction in which glucose-6-phosphate is converted into 6-phosphogluconolactone by the enzyme glucose-6-phosphate dehydrogenase.…”