Arsenic trioxide (As₂O₃) inhibits invasion of HT1080 human fibrosarcoma cells: Role of nuclear factor‐κB and reactive oxygen species

Abstract

In order to define the role of As2O3 in regulating the tumor cell invasiveness, the effects of As2O3 on secretion of matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA), and in vitro invasion of HT1080 human fibrosarcoma cells were examined. As2O3 inhibited cell adhesion to the collagen matrix in a concentration dependent manner, whereas the same treatment enhanced cell to cell interaction. In addition, As2O3 inhibited migration and invasion of HT1080 cells stimulated with phorbol 12-myristate 13-aceate (PMA), and suppressed the expression of MMP-2, -9, membrane type-1 MMP, uPA, and uPA receptor (uPAR). In contrast, As2O3 increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and PA inhibitor (PAI)-1, and reduced the MMP-2, -9, and uPA promoter activity in the presence and absence of PMA. Furthermore, the promoter stimulating and DNA binding activity of nuclear factor-kappaB (NF-kappaB) was blocked by As2O3, whereas the activator protein-1 activity was unchanged. Pretreatment of the cells with N-acetyl-L-cysteine (NAC) significantly prevented suppression of MMPs and uPA secretion, DNA binding activity of NF-kappaB, and in vitro invasion of HT1080 cells by As2O3, suggesting a role of reactive oxygen species (ROS) in this process. These results suggest that As2O3 inhibits tumor cell invasion by modulating the MMPs/TIMPs and uPA/uPAR/PAI systems of extracellular matrix (ECM) degradation. In addition, the generation of ROS and subsequent suppression of NF-kappaB activity by As2O3 might partly be responsible for the phenomena. Overall, As2O3 shows potent activity controlling tumor cell invasiveness in vitro.

Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model

“…5,31,32 Zymography is often used to measure MMP-2 level and activity of the conditioned medium, and the result indicates a positive correlation with the cell invasion capacity. 33,34 We found that the Ad-REIC treatment inhibited the level of extracellular MMP-2 in RM-9 cells when determined by zymography, indicating that the suppressed in vitro invasion and in vivo metastasis are attributed to the downregulated MMP-2 activity, at least in part. As both the pro and active forms of MMP-2 were suppressed, it is conceivable that the Ad-REIC treatment could inhibit both MMP synthesis and activity.…”

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

“…With reference to a number of data reporting an anti-invasive effect of TIMP-1 on cancer cell invasion [23,[25][26][27][28][29][30][31], the present work focussed on the causal link of cannabinoid receptor- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 An invasion-associated effect that is mainly determined by the ability of cancer cells to secrete matrix-degrading enzymes or to modulate their activity rather than on cellular motility was substantiated by the finding that reduced Matrigel invasion was not associated with a decrease of transmigration through uncoated Boyden chambers after cannabidiol treatment.…”

“…[24]). Among the four distinct members of the TIMP family, elevated TIMP-1 was shown to mediate the anti-invasive effects of several anticarcinogenic drugs [23,[25][26][27][28][29]. Furthermore, decreased TIMP-1 levels were demonstrated to correlate with high cancer invasiveness [30,31].…”

Gallic acid suppresses the migration and invasion of PC-3 human prostate cancer cells via inhibition of matrix metalloproteinase-2 and -9 signaling pathways

“…6E). TIMP1 has been shown to regulate MMP2 activity and numerous pieces of evidence have indicated a correlation between elevated TIMP1 levels and diminished MMP-2 activity and invasiveness (46)(47)(48).…”