Long-term exposure of human renal carcinoma cells to PD98059 induces epithelial–mesenchymal transition-like phenotype and enhanced motility

Kanda, Shigeru; Kanetake, Hiroshi; Miyata, Yasuyoshi

doi:10.1007/s11010-007-9644-x

Cited by 4 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we demonstrated that stimulation with IL‐6 led to the activation of STAT3, AKT, ERK1/2 signaling pathways in AM‐EpiCs; however, only specifically blocking ERK1/2 or STAT3 signaling significantly abrogated IL‐6‐mediated EMT‐ and stem cell‐related gene expression in these cells. Of note, blocking ERK1/2 activity alone by PD98059 treatment induced the expression of certain EMT‐related markers in AM‐EpiCs, which was consistent with a previous study by Kanda et al, reporting that exposure to PD98059 increased cell motility by promoting EMT in human renal carcinoma cells . Since ERK and STAT3 were involved in a variety of tumor cell responses, inhibition of these signaling pathways was considered a potential strategy in the treatment of advanced cancer .…”

Section: Discussionsupporting

confidence: 88%

Mesenchymal Stromal Cell-Derived Interleukin-6 Promotes Epithelial–Mesenchymal Transition and Acquisition of Epithelial Stem-Like Cell Properties in Ameloblastoma Epithelial Cells

et al. 2017

View full text Add to dashboard Cite

Epithelial-mesenchymal transition (EMT), a biological process associated with cancer stem-like or cancer-initiating cell formation, contributes to the invasiveness, metastasis, drug resistance, and recurrence of the malignant tumors; it remains to be determined whether similar processes contribute to the pathogenesis and progression of ameloblastoma (AM), a benign but locally invasive odontogenic neoplasm. Here, we demonstrated that EMT- and stem cell-related genes were expressed in the epithelial islands of the most common histologic variant subtype, the follicular AM. Our results revealed elevated interleukin (IL)-6 signals that were differentially expressed in the stromal compartment of the follicular AM. To explore the stromal effect on tumor pathogenesis, we isolated and characterized both mesenchymal stromal cells (AM-MSCs) and epithelial cells (AM-EpiCs) from follicular AM and demonstrated that, in in vitro culture, AM-MSCs secreted a significantly higher level of IL-6 as compared to the counterpart AM-EpiCs. Furthermore, both in vitro and in vivo studies revealed that exogenous and AM-MSC-derived IL-6 induced the expression of EMT- and stem cell-related genes in AM-EpiCs, whereas such effects were significantly abrogated either by a specific inhibitor of STAT3 or ERK1/2, or by knockdown of Slug gene expression. These findings suggest that AM-MSC-derived IL-6 promotes tumor-stem like cell formation by inducing EMT process in AM-EpiCs through STAT3 and ERK1/2-mediated signaling pathways, implying a role in the etiology and progression of the benign but locally invasive neoplasm. Stem Cells 2017;35:2083-2094.

show abstract

Section: Discussionsupporting

confidence: 88%

Mesenchymal Stromal Cell-Derived Interleukin-6 Promotes Epithelial–Mesenchymal Transition and Acquisition of Epithelial Stem-Like Cell Properties in Ameloblastoma Epithelial Cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…ERK is activated by mitogen‐activated protein kinase ERK kinases (MEK 1 and 2), the only upstream molecules that can phosphorylate ERK. In vitro , PD98059, a MEK inhibitor, was found to decrease tumour cell proliferation by potentiating the cytotoxicity of chemotherapy in leukaemia, small cell lung cancer, cervical cancer, and colorectal cancer, while U0126, another MEK inhibitor, was shown to inhibit melanoma metastases 33–36. The reasons for the poor outcome of MEK inhibition in patients with advanced cancer are unknown 33.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro , PD98059, a MEK inhibitor, was found to decrease tumour cell proliferation by potentiating the cytotoxicity of chemotherapy in leukaemia, small cell lung cancer, cervical cancer, and colorectal cancer, while U0126, another MEK inhibitor, was shown to inhibit melanoma metastases 33–36. The reasons for the poor outcome of MEK inhibition in patients with advanced cancer are unknown 33. In endometriosis, PD98059 decreases the in vitro production of pro‐inflammatory cytokines in endometriotic cells and decreases the in vitro viability of stromal eutopic endometrial cells 16, 25, 28.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo

Ngô

Nicco

Leconte

et al. 2010

The Journal of Pathology

View full text Add to dashboard Cite

Endometriosis affects 6-10% of women in their reproductive years, causing chronic pelvic pain and infertility. Its pathogenesis remains poorly understood and current treatments, based on hormonal therapy or surgery, are often insufficient. The purpose of our study was to investigate the role of the ERK pathway in the development of endometriosis and to test the effects of protein kinase inhibitors on the proliferation of endometriotic cells in vitro and in vivo. We studied ex vivo human endometrial and endometriotic cells in culture. Stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from patients with endometriosis and from patients without endometriosis. The ERK pathway was explored by western blot on cell lysates and by ELISA on total crushed specimens of endometrium. Cells in culture were treated with A771726, PD98059, and U0126. Human endometriotic lesions were implanted in nude mice. Mice were treated with A771726, leflunomide, PD98059, U0126 or PBS during 2 weeks before sacrifice and extraction of the endometriotic implants for histological examination. We found that the ERK pathway was significantly activated in endometriotic cells and in endometrial cells from patients with endometriosis compared to endometrial cells of control patients, both by ELISA and by western blot. This phenomenon was associated with an increased proliferation of endometriotic cells compared to endometrial cells. Treating endometriotic cells with A771726, PD98059 or U0126 abrogated the phosphorylation of ERK and significantly decreased the cellular proliferation in vitro. In vivo, A771726, leflunomide, PD98059, and U0126 controlled the growth of endometriotic implants in the mouse model of endometriosis. Our study shows that protein kinase inhibitors could be new candidates to treat endometriosis. However, further studies are needed to evaluate their effects and tolerability in humans.

show abstract

“…Indeed, U0126 showed a slight effect on cell contraction. ERK1/2 effects could be mediated through tropomyosin phosphorylation in response to oxidative stress [27] or downregulating RhoA/Rho Kinase signalling [28]. Of note, changes in RhoA activity early during reoxygenation have been previously observed in our H/R model [5] even though further experiments should be done to clarify this relationship.…”

Section: Discussionmentioning

confidence: 63%

ERK1/2 Mediates Cytoskeleton and Focal Adhesion Impairment in Proximal Epithelial Cells after Renal Ischemia

Sáenz-Morales¹,

Conde

Escribese

et al. 2009

Cell Physiol Biochem

View full text Add to dashboard Cite

ERK1/2 has been reported to be activated in the postischemic kidney but its precise role in ischemia/reperfusion (I/R) injury remains unclear. Therefore, we have studied the expression of ERK1/2 and its contribution to cytoskeleton organization and cell adhesion structures in proximal tubular cells, all affected during I/R. We observe ERK1/2 activation at 24 hours of reperfusion in an in vivo model of I/R, when acute tubular necrosis (ATN) is most prominent. In addition, by means of an in vitro model of hypoxia/reoxygenation (H/R) in rat proximal NRK-52E cells we show that p-ERK1/2 is strongly induced early during reoxygenation. Moreover, we also demonstrate that ROS generation contributed to this induction. ERK1/2 activation is contemporary with cell-cell adhesion disruption during reoxygenation but the use of U0126 did not have effect on adherens junctions (AJ) and tight junctions (TJ) disassembly, neither on epithelial monolayer permeability. On the contrary, ERK1/2 affects cytoskeleton organization and focal complexes assembly during H/R, since U0126 improved actin and tubulin cytoskeleton structure, reduced cell contraction and prevented paxillin redistribution. In summary, ERK1/2 signalling plays an essential role in I/R induced injury, mediating proximal cell adhesive alterations which lead to tubular damage and ultimately might compromise renal function.

show abstract

Long-term exposure of human renal carcinoma cells to PD98059 induces epithelial–mesenchymal transition-like phenotype and enhanced motility

Cited by 4 publications

References 21 publications

Mesenchymal Stromal Cell-Derived Interleukin-6 Promotes Epithelial–Mesenchymal Transition and Acquisition of Epithelial Stem-Like Cell Properties in Ameloblastoma Epithelial Cells

Mesenchymal Stromal Cell-Derived Interleukin-6 Promotes Epithelial–Mesenchymal Transition and Acquisition of Epithelial Stem-Like Cell Properties in Ameloblastoma Epithelial Cells

Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo

ERK1/2 Mediates Cytoskeleton and Focal Adhesion Impairment in Proximal Epithelial Cells after Renal Ischemia

Contact Info

Product

Resources

About