Thioredoxin stimulates MMP-9 expression, de-regulates the MMP-9/TIMP-1 equilibrium and promotes MMP-9 dependent invasion in human MDA-MB-231 breast cancer cells

Farina, Antonietta R.; Cappabianca, Lucia; DeSantis, Giuseppina; Ianni, Natalia Di; Ruggeri, Pierdomenico; Ragone, Marzia; Merolle, Stefania; Tonissen, Kathryn Fay; Gulino, Alberto; Mackay, Andrew R.

doi:10.1016/j.febslet.2011.09.023

Cited by 48 publications

(38 citation statements)

References 37 publications

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“…17) In contrast, the deregulation of the MMP-9/ TIMP-1 equilibrium has facilitated the invasion of human MDA-MB-231 breast cancer cells. 25) In the present study, we demonstrated that p-cymene transcriptionally augments the production of TIMP-1 in TPA-stimulated HT-1080 cells, under which the invasiveness of HT-1080 cells was attenuated. Thus, these results suggest a possible mechanism in that the antitumor invasive activity of p-cymene includes not only the down-regulation of MMP-9 production but also the up-regulation of TIMP-1 production.…”

Section: Discussionsupporting

confidence: 55%

Novel Antitumor Invasive Actions of <i>p</i>-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells

Liu

Sato

2016

Biological & Pharmaceutical Bulletin

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p-Cymene (4-isopropyltoluene) has been reported to have beneficial actions such as anti-inflammatory and antinociceptive activities. To evaluate whether p-cymene exhibits antitumor invasive actions, we examined the effects of p-cymene on the production of matrix metalloproteinase 9 (MMP-9)/gelatinase B and tissue inhibitor of metalloproteinases-1 (TIMP-1) in human fibrosarcoma HT-1080 cells. p-Cymene was found to dose-dependently inhibit the 12-O-tetradecanoylphorbol 13-acetate (TPA)-augmented production and gene expression of MMP-9 in HT-1080 cells. In contrast, p-cymene enhanced the TPA-augmented production and gene expression of TIMP-1 in HT-1080 cells. However, there was no change in the constitutive level of MMP-9 and TIMP-1 mRNAs and TIMP-1 protein in p-cymene-treated cells. In addition, we found that the in-vitro TPA-augmented invasiveness of HT-1080 cells was inhibited by p-cymene in a dose-dependent manner. Furthermore, p-cymene was found to suppress the constitutive and/or TPA-augmented phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) in HT-1080 cells. Thus, these results provide novel evidence that p-cymene is an effective candidate for the prevention of tumor invasion and metastasis through mechanisms that include the inhibition of MMP-9 expression and the augmentation of TIMP-1 production along with the suppression of ERK1/2 and p38 MAPK signal pathways in tumor cells.Key words p-cymene; tumor invasion; matrix metalloproteinase 9; tissue inhibitor of metalloproteinases-1; extracellular signal-regulated kinase 1/2 (ERK1/2); p38 mitogen-activated protein kinase (p38 MAPK)The proteolytic degradation of extracellular matrix (ECM) components in basement membranes and stroma tissues is requisite for progressing the invasion and metastasis of malignant tumor cells. Matrix metalloproteinases (MMPs) play a crucial role in ECM degradation, and different sets of MMPs concertedly act in ECM breakdown. 1,2) Gelatinase A (72-kDa type IV collagenase)/MMP-2 and gelatinase B (92-kDa type IV collagenase)/MMP-9 have been reported to facilitate tumor cell invasion and epithelial-mesenchymal transition as a promoter and/or modulator in normal and tumor cells in vivo and in vitro.3) On the other hand, the enzymic activity of MMPs and proteolytic activation of the MMP precursor (proMMP) have been reported to be controlled by endogenous inhibitors such as tissue inhibitors of metalloproteinases (TIMPs).4) Since four TIMPs have been identified, designated as TIMP-1, TIMP-2, TIMP-3, and TIMP-4, they inhibit MMPs by forming a strong noncovalent complex with a 1 : 1 stoichiometry. 4) Regarding the inhibitory properties among the TIMPs, TIMPs can bind to different sets of MMPs: e.g., the preference inhibition of TIMP-1 against MMP-9, MMP-3, and MMP-1, and that of TIMP-2 against MMP-2 rather than MMP-9.4,5) Therefore, the inhibition of expression and/or enzymic activity of MMP is likely to be an effective target(s) for preventing tumor invasion and metastasis.

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Section: Discussionsupporting

confidence: 55%

Novel Antitumor Invasive Actions of <i>p</i>-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells

Liu

Sato

2016

Biological & Pharmaceutical Bulletin

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“…Extracellular thioredoxin has been suggested to have chemotactic activity and to act as chemo-attractant for neutrophils, monocytes and Tcells [24]. Extracellular thioredoxin has also been associated with cancer cell metastasis [25] and the promotion of a matrix metalloproteinase-9 (MMP-9) dependent invasive phenotype in malignant breast cancer cells [26].…”

Section: Subcellular Localisation and Functions Of Thioredoxinmentioning

confidence: 99%

“…Thioredoxin enhances the invasive behavior of tumor cells by regulating MMP activity, which is required for ECM degradation [25,26]. HIF-1 over-expression during hypoxia has also been associated with ECM degradation by upregulating MMP-2 [94] and MMP-9 gene expression [95].…”

Section: The Interaction Of Redox and Hypoxic Pathways Under Intermitmentioning

confidence: 99%

The Interaction Between Redox and Hypoxic Signalling Pathways in the Dynamic Oxygen Environment of Cancer Cells

Bhatia¹,

Karlenius²,

Trapani³

et al. 2013

Carcinogenesis

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“…8 In addition, Trx upregulated the protease MMP-9 via NFκB, facilitating tumor cell invasion. 27 In fact, distinct subcellular localizations of Trx were already described for cancer as compared with normal tissues in other tumor entities. 28,29 In gallbladder carcinomas, patients with nuclear Trx showed shorter survival than patients without nuclear Trx.…”

Section: Discussionmentioning

confidence: 95%

Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity

Ahrens

Timme

Ostendorp

et al. 2016

Laboratory Investigation

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We previously showed that histone deacetylase inhibitor (HDACi) and 5-azacytidine (AZA) treatment selectively induced cell death of esophageal cancer cells. The mechanisms of cancer selectivity, however, remained unclear. Here we examined whether the cancer selectivity of HDACi/AZA treatment is mediated by the thioredoxin (Trx) system and reactive oxygen species (ROS) in esophageal cancer cells. For this, we first analyzed human tissue specimens of 37 esophageal cancer patients by immunohistochemistry for Trx, Trx-interacting protein (TXNIP) and Trx reductase (TXNRD). This revealed a loss or at least reduction of nuclear Trx in esophageal cancer cells, compared with normal epithelial cells (Po0.001). Although no differences were observed for TXNIP, TXNRD was more frequently expressed in cancer cells (Po0.001). In the two main histotypes of esophageal squamous cell carcinomas (ESCCs, n = 19) and esophageal adenomcarcinomas (EAC, n = 16), similar Trx, TXNIP and TXNRD expression patterns were observed. Also in vitro, nuclear Trx was only detectable in non-neoplastic Het-1A cells, but not in OE21/ESCC or OE33/EAC cell lines. Moreover, the two cancer cell lines showed an increased Trx activity, being significant for OE21 (P = 0.0237). After treatment with HDACi and/or AZA, ROS were exclusively increased in both cancer cell lines (P = 0.048-0.017), with parallel decrease of Trx activity. This was variably accompanied by increased TXNIP levels upon AZA, MS-275 or MS-275/AZA treatment for 6 or 24 h in OE21, but not in Het-1A or OE33 cells. In summary, this study evaluated Trx and its associated proteins TXNIP and TXNRD for the first time in esophageal cancers. The analyses revealed an altered subcellular localization of Trx and strong upregulation of TXNRD in esophageal cancer cells. Moreover, HDACi and AZA disrupted Trx function and induced accumulation of ROS with subsequent apoptosis in esophageal cancer cells exclusively. Trx function is hence an important cellular mediator conferring non-neoplastic cell resistance for HDACi and/or AZA.

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Thioredoxin stimulates MMP-9 expression, de-regulates the MMP-9/TIMP-1 equilibrium and promotes MMP-9 dependent invasion in human MDA-MB-231 breast cancer cells

Cited by 48 publications

References 37 publications

Novel Antitumor Invasive Actions of <i>p</i>-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells

Novel Antitumor Invasive Actions of <i>p</i>-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells

The Interaction Between Redox and Hypoxic Signalling Pathways in the Dynamic Oxygen Environment of Cancer Cells

Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity

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