Cyclooxygenase-2 promotes ovarian cancer cell migration and cisplatin resistance via regulating epithelial mesenchymal transition

Background Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.

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Conditioned media from human ovarian cancer endothelial progenitor cells induces ovarian cancer cell migration by activating epithelial-to-mesenchymal transition

Cancer Gene Therapy ◽

10.1038/cgt.2015.45 ◽

2015 ◽

Vol 22 (11) ◽

pp. 518-523 ◽

Cited By ~ 4

Author(s):

L Teng ◽

S Peng ◽

H Guo ◽

H Liang ◽

Z Xu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Cancer Cell ◽

Epithelial To Mesenchymal Transition ◽

Ovarian Cancer Cell ◽

Human Ovarian Cancer ◽

Cancer Cell Migration ◽

Mesenchymal Transition

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Faculty Opinions recommendation of Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13361012.14731132 ◽

2011 ◽

Author(s):

Alexey Tepikin

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Protein Kinase ◽

Protein Kinase A ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Migration And Invasion ◽

Cancer Cell Migration ◽

Cell Migration And Invasion ◽

Kinase A

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Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

Endocrine Related Cancer ◽

10.1677/erc-09-0152 ◽

2010 ◽

Vol 17 (2) ◽

pp. 335-349 ◽

Cited By ~ 29

Author(s):

Inga Mertens-Walker ◽

Christine Bolitho ◽

Robert C Baxter ◽

Deborah J Marsh

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Protein Kinase ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Migration ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Gf 109203X ◽

Cell Migration And Proliferation

The gonadotropin hypothesis proposes that elevated serum gonadotropin levels may increase the risk of epithelial ovarian cancer (EOC). We have studied the effect of treating EOC cell lines (OV207 and OVCAR-3) with FSH or LH. Both gonadotropins activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and increased cell migration that was inhibited by the MAPK 1 inhibitor PD98059. Both extra- and intracellular calcium ion signalling were implicated in gonadotropin-induced ERK1/2 activation as treatment with either the calcium chelator EGTA or an inhibitor of intracellular calcium release, dantrolene, inhibited gonadotropin-induced ERK1/2 activation. Verapamil was also inhibitory, indicating that gonadotropins activate calcium influx via L-type voltage-dependent calcium channels. The cAMP/protein kinase A (PKA) pathway was not involved in the mediation of gonadotropin action in these cells as gonadotropins did not increase intracellular cAMP formation and inhibition of PKA did not affect gonadotropin-induced phosphorylation of ERK1/2. Activation of ERK1/2 was inhibited by the protein kinase C (PKC) inhibitor GF 109203X as well as by the PKCδ inhibitor rottlerin, and downregulation of PKCδ was inhibited by small interfering RNA (siRNA), highlighting the importance of PKCδ in the gonadotropin signalling cascade. Furthermore, in addition to inhibition by PD98059, gonadotropin-induced ovarian cancer cell migration was also inhibited by verapamil, GF 109203X and rottlerin. Similarly, gonadotropin-induced proliferation was inhibited by PD98059, verapamil, GF 109203X and PKCδ siRNA. Taken together, these results demonstrate that gonadotropins induce both ovarian cancer cell migration and proliferation by activation of ERK1/2 signalling in a calcium- and PKCδ-dependent manner.

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