Inhibition of Raf-MEK-ERK and Hypoxia pathways by Phyllanthus prevents metastasis in human lung (A549) cancer cell line

Lee, Sau Har; Jaganath, Indu Bala; Manikam, Rishya; Sekaran, Shamala Devi

doi:10.1186/1472-6882-13-271

Cited by 29 publications

(15 citation statements)

References 59 publications

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“… 34 , 35 Regulation of metastasis by MAPK is mainly via controlling the cells' expression of MMPs enzymes by decreasing the nuclear levels of NF- κ B, c-Fos or c-Jun. 33 , 36 The present study shows that hsa-miR-623 overexpression leads to significantly reduction in the expressions of Ku80, p-ERK, p-JNK, MMP-2/9 and reduces lung adenocarcinoma cell invasion. Moreover, it is established that hsa-miR-623 inhibition increases Ku80 expression, leads to ERK/JNK family activation, and increases tumor invasion.…”

Section: Discussionsupporting

confidence: 52%

RETRACTED ARTICLE: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma

Wei

Zhang

et al. 2016

Cell Death Dis

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Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.

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Section: Discussionsupporting

confidence: 52%

RETRACTED ARTICLE: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma

Wei

Zhang

et al. 2016

Cell Death Dis

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“…A report indicated that the activation of ERK signaling skewing macrophage polarization away from the M1-to a tumor-promoting M2-like phenotype, and high density of M2 macrophages was associated with metastasis in NSCLC patients (22). Previous research also demonstrated that suppressing ERK1/2 led to suppression of various critical proteins for A549 invasion and migration (44). The results in this study indicated that puerarin restrained the activation of MEK/ERK 1/2 pathway through inhibition of ERK nucleus translocation.…”

Section: Discussionmentioning

confidence: 99%

Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway

Kang

Zhang

Bao-zhong

et al. 2017

International Journal of Oncology

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Non-small cell lung carcinoma (NSCLC) metastasis is responsible for most of cancer-related mortality. The tumor associated macrophages (TAMs) are known to be crucial cells in lung cancer and are usually divided into two antagonistic types, M1 and M2. Puerarin has a wide spectrum of pharmacological properties. The present study explores puerarin on macrophage polarization and metastasis of NSCLC. The results demonstrated that puerarin inhibited tumor growth and tumor volumes in NSCLC xenograft model, increased M1 markers [CD197+, inducible nitric oxide synthase (iNOS)+, CD40+)] and reduced M2 markers (CD206+, Arg-1+ and CD163+). Besides, puerarin elevated the level of pro-inflammatory cytokine interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-12, decreased the expression of pro-tumor cytokines IL-10, IL-4 and transforming growth factor (TGF)-β. To explore whether puerarin directly acts on macrophages, we purified macrophages from NSCLC model, the results showed that puerarin inhibited macrophages polarized to M2 phenotype and did not require the auxiliary of other cells. In addition, puerarin suppressed the invasion and migration of NSCLC macrophages, restrained the expression of angiogenesis factors. Puerarin also inhibited the activation of mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) 1/2 pathway through inhibition of ERK nucleus translocation. Finally, IL-4 induced M2 macrophage polarization and metastasis were partially offset by puerarin through inactivating the MEK/ERK 1/2 pathway. Taken together, this study validated that puerarin is able to skew macrophage populations back to M1 subsets to stimulate antitumor effects and suggests puerarin is a negative metastatic regulator of NSCLC.

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“…The suppression of ERK1/2 and hypoxia pathways resulted in the suppression of MMP-2, MMP-9, and MMP-7 expression in A549 cell metastasis ( 39 ). Metalloproteinases, particularly MMP-2, play an important role in the regulation of fundamental cancer cellular processes including cell growth, invasion, inflammation and angiogenesis ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

The synergistic effect of propofol and ulinastatin suppressed the viability of the human lung adenocarcinoma epithelial A549 cell line

Guo

Chen

et al. 2018

Oncol Lett

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Ulinastatin and propofol (PPF) are recognized for their anticancer properties. The aim of the present study was to evaluate the synergistic antitumor effect of PPF followed by ulinastatin against A549 cells. In MTT assays, PPF (10, 20 and 30 µM) followed by 200 U/ml ulinastatin was more effective at inhibiting A549 cell viability compared with PPF (10, 20 and 30 µM) or 200 U/ml ulinastatin. PPF (10, 20 and 30 µM) followed by 200 U/ml ulinastatin treatments synergistically increased the number of S cells and synergistically reduced the number of G2/M cells associated with PPF stimulation in a dose-dependent manner. Western blot analysis demonstrated that the antitumor effect of PPF followed by 200 U/ml ulinastatin treatments were associated with the downregulated expression of extracellular signal-regulated kinase 1 and 2 phosphorylation (p-ERK1/2) and matrix metalloproteinases 2 (MMP-2). In conclusion, these data demonstrated that PPF (20 and 30 µM) followed by 200 U/ml ulinastatin treatments synergistically stimulated a significant proportion of A549 cells in S phase. Furthermore, the combination synergistically reduced a significant proportion of A549 cells in G2/M phase and synergistically suppressed the viability of A549 cells, which was possibly related regulation of the expression of p-ERK1/2 and MMP-2 in A549 cells.

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Inhibition of Raf-MEK-ERK and Hypoxia pathways by Phyllanthus prevents metastasis in human lung (A549) cancer cell line

Cited by 29 publications

References 59 publications

RETRACTED ARTICLE: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma

RETRACTED ARTICLE: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma

Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway

The synergistic effect of propofol and ulinastatin suppressed the viability of the human lung adenocarcinoma epithelial A549 cell line

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