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. 2021 Jul 21:8:1530-1537.
doi: 10.1016/j.toxrep.2021.07.012. eCollection 2021.

Inhibition of PKC/MEK pathway suppresses β1-integrin and mitigates breast cancer cells proliferation

Nahla E El-Ashmawy  1 , Enas A El-Zamarany  2 , Naglaa F Khedr  1 , Hend M Selim  1 , Eman G Khedr  1
Affiliations

Inhibition of PKC/MEK pathway suppresses β1-integrin and mitigates breast cancer cells proliferation

Nahla E El-Ashmawy et al. Toxicol Rep. .

Abstract

Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.

Keywords: Breast cancer; E2F1; FOXC2; NF-ҡB; Prostaglandin E2; β1-integrin.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Cell cycle analysis of the studied groups. a: Control group, b: EP1 agonist, c: EP1 antagonist +EP1 agonist, d: MEK inhibitor+EP1 agonist, e: PKC inhibitor +EP1 agonist and f: NF-ҡB inhibitor+EP1 agonist. EP1: E prostanoid receptor 1, MEK: Mitogen activated protein kinase kinase, PKC: Protein kinase C, NF-ҡB: Nuclear factor kappa -light-chain-enhancer of activated B cells. Apop: Apoptosis ; G0/G1: Gap phase G0 and G1 ; S: Synthesis phase; G2/M: Gap phase 2 and Mitosis phase. PIPE-A: Propidium Iodide Phycoerythrin Area.
Fig. 2
Fig. 2
Effect of treatments on FOXC2 level in breast cancer cell line. Data are presented as mean ± SD. a: Significant versus control group. b: Significant versus EP1 agonist group. n = 6 replicates. EP1: E prostanoid receptor 1, MEK: Mitogen activated protein kinase kinase, PKC: Protein kinase C, NF-ҡB: Nuclear factor kappa-light-chain-enhancer of activated B cells, FOXC2: Forkhead box protein C2.
Fig. 3
Fig. 3
Effect of treatments on E2F1 level in breast cancer cell line. Data are presented as mean ± SD. a: Significant versus control group. b: Significant versus EP1 agonist group. n = 6 replicates. EP1: E prostanoid receptor 1, MEK: Mitogen activated protein kinase kinase, Protein kinase C, NF-ҡB: Nuclear factor kappa-light-chain-enhancer of activated B cells, E2F1: E2F Transcription Factor 1.
Fig. 4
Fig. 4
Effect of treatments on total and phosphorylated NF-ҡB p65 level in breast cancer cell line. Data are presented as mean±SD. a: Significant versus control group. b: Significant versus EP1 agonist group. n = 6 replicates. EP1: E prostanoid receptor 1, MEK: Mitogen activated protein kinase kinase, PKC: Protein kinase C, NF-ҡB: Nuclear factor kappa-light-chain-enhancer of activated B cells.
Fig. 5
Fig. 5
Effect of treatments on Survivin level in breast cancer cell line. Data are presented as mean ± SD. a: Significant versus control group. b: Significant versus EP1 agonist group. n = 6 replicates. EP1: E prostanoid receptor 1, MEK: Mitogen activated protein kinase kinase, PKC: Protein kinase C, NF-ҡB: Nuclear factor kappa-light-chain-enhancer of activated B cells.
Fig. 6
Fig. 6
Effect of treatments on β1- integrin gene expression in breast cancer cell line. Data are presented as mean ± SD. a: Significant versus control group. b: Significant versus EP1 agonist group. n = 6 replicates. EP1: E prostanoid receptor 1, MEK: Mitogen activated protein kinase kinase, PKC: Protein kinase C, NF-ҡB: nuclear factor kappa-light-chain-enhancer of activated B cells.
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References

    1. Bazzani L., Donnini S., Finetti F., Christofori G., Ziche M. PGE2/EP3/SRC signaling induces EGFR nuclear translocation and growth through EGFR ligands release in lung adenocarcinoma cells. Oncotarget. 2017;8(19):31270–31287. - PMC - PubMed
    1. de Almeida V., Santos Guimarães I., Almendra L.R., Rondon A.M.R., Tilli T.M., de Melo A.C., Sternberg C., Monteiro R.Q. Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer. Oncotarget. 2018;9:30594–30609. - PMC - PubMed
    1. Chen E.P., Smyth E.M. COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins Other Lipid Mediat. 2011;96:14–20. - PMC - PubMed
    1. Ma J., Chen M., Xia S., Shu W., Guo Y., Wang Y., Xu Y., Bai X., Zhang L., Zhang H., Zhang M., Wang Y., Leng J. Prostaglandin E2 promotes liver cancer cell growth by the upregulation of FUSE-binding protein 1 expression. Int. J. Oncol. 2013;42(3):1093–1104. - PubMed
    1. Reader J., Holt D., Fulton A. Prostaglandin E2 EP receptors as therapeutic targets in breast cancer. Cancer Metastasis Rev. 2011;30(3-4):449–463. - PMC - PubMed