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Lipoxin A4 Attenuates Cell Invasion by Inhibiting ROS/ERK/MMP Pathway in Pancreatic Cancer.

Zong L, Li J, Chen X, Chen K, Li W, Li X, Zhang L, Duan W, Lei J, Xu Q, Shan T, Ma Q, Sun H - Oxid Med Cell Longev (2015)

Bottom Line: Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2.Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-L-cysteine (NAC).However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.

ABSTRACT
Lipoxin A4 (LXA4), an endogenous arachidonic acid metabolite, was previously considered an anti-inflammatory lipid mediator. But it also has the potential to inhibit cancer progression. To explore the therapeutic effect of LXA4 in pancreatic cancer, we used Panc-1 cells to investigate the mechanism by which LXA4 can attenuate pancreatic cancer cell invasion. Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2. Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-L-cysteine (NAC). However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204. The blocking of either intracellular ROS or ERK pathway caused the downregulation of MMP-9 and MMP-2 expression. Furthermore, tests revealed that LXA4 inhibited MMP-9 and MMP-2 at the mRNA, protein, and functional levels. Finally, LXA4 dramatically limited the invasion of CoCl2-mimic hypoxic cells and abrogated intracellular ROS levels, ERK activity, and MMPs expression. These results suggest that LXA4 attenuates cell invasion in pancreatic cancer by suppressing the ROS/ERK/MMPs pathway, which may be beneficial for preventing the invasion of pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus

LXA4 downregulated MMP-9 and MMP-2 mRNA transcription. (a) Secretion of MMP-9 and MMP-2 influenced by LXA4, NAC, or FR180204. Cells were cultured with FBS-free medium for 24 hours and then MMP-9 and MMP-2 secreted into mediums normalized by cell number were tested by ELISA. (b) Western blot analysis of MMP-9 and MMP-2 in Panc-1 cells treated like above. (c) Transcription of MMP-9 and MMP-2 tested by RT-qPCR.  ∗P < 0.05 versus vehicle control.
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fig4: LXA4 downregulated MMP-9 and MMP-2 mRNA transcription. (a) Secretion of MMP-9 and MMP-2 influenced by LXA4, NAC, or FR180204. Cells were cultured with FBS-free medium for 24 hours and then MMP-9 and MMP-2 secreted into mediums normalized by cell number were tested by ELISA. (b) Western blot analysis of MMP-9 and MMP-2 in Panc-1 cells treated like above. (c) Transcription of MMP-9 and MMP-2 tested by RT-qPCR.  ∗P < 0.05 versus vehicle control.

Mentions: Our previous data demonstrated that LXA4 could inhibit cell invasion via the downregulation of MMP-9/MMP-2 and the suppression of ROS/ERK pathway. However, it still needed to investigate how LXA4 influenced the expression of MMPs. Thus we performed ELISA assay to test secreted MMPs, which showed fewer amounts MMP-9 and MMP-2 were secreted by cells treated with LXA4 (Figure 4(a)). At the protein level, as previous data (Figure 4(b)) have shown, MMPs were expressed to a lesser extent in the LXA4-treated group. Eventually, RT-qPCR demonstrated that LXA4 could downregulate MMP-9 and MMP-2 at the transcriptional level (Figure 4(c)).


Lipoxin A4 Attenuates Cell Invasion by Inhibiting ROS/ERK/MMP Pathway in Pancreatic Cancer.

Zong L, Li J, Chen X, Chen K, Li W, Li X, Zhang L, Duan W, Lei J, Xu Q, Shan T, Ma Q, Sun H - Oxid Med Cell Longev (2015)

LXA4 downregulated MMP-9 and MMP-2 mRNA transcription. (a) Secretion of MMP-9 and MMP-2 influenced by LXA4, NAC, or FR180204. Cells were cultured with FBS-free medium for 24 hours and then MMP-9 and MMP-2 secreted into mediums normalized by cell number were tested by ELISA. (b) Western blot analysis of MMP-9 and MMP-2 in Panc-1 cells treated like above. (c) Transcription of MMP-9 and MMP-2 tested by RT-qPCR.  ∗P < 0.05 versus vehicle control.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4663743&req=5

fig4: LXA4 downregulated MMP-9 and MMP-2 mRNA transcription. (a) Secretion of MMP-9 and MMP-2 influenced by LXA4, NAC, or FR180204. Cells were cultured with FBS-free medium for 24 hours and then MMP-9 and MMP-2 secreted into mediums normalized by cell number were tested by ELISA. (b) Western blot analysis of MMP-9 and MMP-2 in Panc-1 cells treated like above. (c) Transcription of MMP-9 and MMP-2 tested by RT-qPCR.  ∗P < 0.05 versus vehicle control.
Mentions: Our previous data demonstrated that LXA4 could inhibit cell invasion via the downregulation of MMP-9/MMP-2 and the suppression of ROS/ERK pathway. However, it still needed to investigate how LXA4 influenced the expression of MMPs. Thus we performed ELISA assay to test secreted MMPs, which showed fewer amounts MMP-9 and MMP-2 were secreted by cells treated with LXA4 (Figure 4(a)). At the protein level, as previous data (Figure 4(b)) have shown, MMPs were expressed to a lesser extent in the LXA4-treated group. Eventually, RT-qPCR demonstrated that LXA4 could downregulate MMP-9 and MMP-2 at the transcriptional level (Figure 4(c)).

Bottom Line: Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2.Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-L-cysteine (NAC).However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.

ABSTRACT
Lipoxin A4 (LXA4), an endogenous arachidonic acid metabolite, was previously considered an anti-inflammatory lipid mediator. But it also has the potential to inhibit cancer progression. To explore the therapeutic effect of LXA4 in pancreatic cancer, we used Panc-1 cells to investigate the mechanism by which LXA4 can attenuate pancreatic cancer cell invasion. Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2. Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-L-cysteine (NAC). However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204. The blocking of either intracellular ROS or ERK pathway caused the downregulation of MMP-9 and MMP-2 expression. Furthermore, tests revealed that LXA4 inhibited MMP-9 and MMP-2 at the mRNA, protein, and functional levels. Finally, LXA4 dramatically limited the invasion of CoCl2-mimic hypoxic cells and abrogated intracellular ROS levels, ERK activity, and MMPs expression. These results suggest that LXA4 attenuates cell invasion in pancreatic cancer by suppressing the ROS/ERK/MMPs pathway, which may be beneficial for preventing the invasion of pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus