Suppression of EGF‐induced tumor cell migration and matrix metalloproteinase‐9 expression by capsaicin via the inhibition of EGFR‐mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP‐1 signaling

Hwang, Yong Pil; Yun, Ho‐Jin; Choi, Jae Ho; Han, Eun Hee; Kim, Hyung Gyun; Song, Gyu Yong; Kwon, Kwang‐il; Jeong, Tae Cheon; Jeong, Hye Gwang

doi:10.1002/mnfr.201000292

Cited by 100 publications

(71 citation statements)

References 37 publications

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“…1B) enabling multiple simultaneous observations. The tumor cells invade in 3D in response to externally applied growth-factor gradients [e.g., epidermal growth factor (EGF) (26,27)] or paracrine signals by the endothelial cells or other stromal cell types [e.g., macrophages (28,29)]. On the 3D ECM-endothelial channel interface, a continuous endothelial monolayer is formed, which enables the observation of intravasation across a hollow vascular lumen, and allows for access to the basal and apical endothelial surfaces through the microchannels.…”

Section: Resultsmentioning

confidence: 99%

Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

Zervantonakis

Hughes

Charest

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

761

695

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Entry of tumor cells into the blood stream is a critical step in cancer metastasis. Although significant progress has been made in visualizing tumor cell motility in vivo, the underlying mechanism of cancer cell intravasation remains largely unknown. We developed a microfluidic-based assay to recreate the tumor-vascular interface in three-dimensions, allowing for high resolution, real-time imaging, and precise quantification of endothelial barrier function. Studies are aimed at testing the hypothesis that carcinoma cell intravasation is regulated by biochemical factors from the interacting cells and cellular interactions with macrophages. We developed a method to measure spatially resolved endothelial permeability and show that signaling with macrophages via secretion of tumor necrosis factor alpha results in endothelial barrier impairment. Under these conditions intravasation rates were increased as validated with live imaging. To further investigate tumor-endothelial (TC-EC) signaling, we used highly invasive fibrosarcoma cells and quantified tumor cell migration dynamics and TC-EC interactions under control and perturbed (with tumor necrosis factor alpha) barrier conditions. We found that endothelial barrier impairment was associated with a higher number and faster dynamics of TC-EC interactions, in agreement with our carcinoma intravasation results. Taken together our results provide evidence that the endothelium poses a barrier to tumor cell intravasation that can be regulated by factors present in the tumor microenvironment.T umor-endothelial cell interactions are critical in multiple steps during cancer metastasis, ranging from cancer angiogenesis to colonization. Cancer cell intravasation is a rate-limiting step in metastasis that regulates the number of circulating tumor cells and thus presents high risk for the formation of secondary tumors (1, 2). During the metastatic process tumor cells migrate out of the primary tumor (3), navigate into a complex tumor microenvironment, and enter into blood vessels (4). Cell-cell communication and chemotaxis (5) are key to this process and can occur via paracrine signals and/or direct contact between different cell types during tumor cell invasion (6) and metastatic colonization (7). Studies using multiphoton imaging in animal models have demonstrated that the ability of tumor cells to enter into the blood stream can be controlled both by tumor cell intrinsic factors (8-11) and other cells present in the tumor microenvironment, such as macrophages (12) and neutrophils (13). However, because of the lack of physiologically relevant in vitro models and the challenges of investigating cell-cell interactions in vivo, the underlying mechanism of intravasation remains poorly understood (14). In particular, a number of fundamental questions remain as to whether intravasation is an active or passive process (15) and whether tumor cells cross the endothelial barrier through cell-cell junctions (paracellular) or through the endothelial cell body [transcellular (16)]. Therefor...

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Section: Resultsmentioning

confidence: 99%

Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

Zervantonakis

Hughes

Charest

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

761

695

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“…6). c-Jun and c-Fos interact to form the activated heterodimeric AP-1 transcriptional factor, which can bind to specific sequences in the promoter regions of many genes, such as N-cadherin [61]. In addition, it was found that both c-Jun and c-Fos occupy the AP-1 site in the N-cadherin promoter in response to UTP, and that the absence of only one AP-1 binding site in the human N-cadherin promoter is sufficient to block the UTP-induced promoter activity of N-cadherin (Fig.…”

Section: Discussionmentioning

confidence: 99%

N-cadherin expression is regulated by UTP in schwannoma cells

Martiáñez

Lamarca

Casals

et al. 2012

Purinergic Signalling

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Schwann cells (SCs) are peripheral myelinating glial cells that express the neuronal Ca 2+ -dependent cell adhesion molecule, neural cadherin (N-cadherin). Ncadherin is involved in glia-glia and axon-glia interactions and participates in many key events, which range from the control of axonal growth and guidance to synapse formation and plasticity. Extracellular UTP activates P2Y purinergic receptors and exerts short-and long-term effects on several tissues to promote wound healing. Nevertheless, the contribution of P2Y receptors in peripheral nervous system functions is not completely understood. The current study demonstrated that UTP induced a dose-and timedependent increase in N-cadherin expression in SCs. Furthermore, N-cadherin expression was blocked by the P2 purinoceptor antagonist suramin. The increased N-cadherin expression induced by UTP was mediated by phosphorylation of mitogen-activated protein kinases (MAPKs), such as Jun N-terminal kinase, extracellular-regulated kinase and p38 kinase. Moreover, the Rho kinase inhibitor Y27632, the phospholipase C inhibitor U73122 and the protein kinase C inhibitor calphostin C attenuated the UTP-induced activation of MAPKs significantly. Extracellular UTP also modulated increased in the expression of the early transcription factors c-Fos and c-Jun. We also demonstrated that the region of the N-cadherin promoter between nucleotide positions −3698 and −2620, which contained one activator protein-1-binding site, was necessary for UTP-induced gene expression. These results suggest a novel role for P2Y purinergic receptors in the regulation of N-cadherin expression in SCs.

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“…Since the Akt and ERK pathways were closely correlated with cell invasion and migration (13,14,(24)(25)(26), the effect of ERK and Akt in the RANKL/ RANK pathway was evaluated. The results showed that sRANKL promoted the activation of ERK and Akt in MCF-7 cells (Fig.…”

Section: Erk and Akt Were Involved In Rankl-induced Breast Cancer Celmentioning

confidence: 99%

“…Findings of previous studies have shown that AKT and ERK1/2 were closely correlated with cell migration (13,14,(24)(25)(26). In mouse B16F10 melanoma cells, pretreatment with the inhibitor of PI3K, PKC, PLC or MEK1/2 suppressed .01 indicate significant difference compared with the control.…”

mentioning

confidence: 94%

C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway

et al. 2011

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Abstract. The receptor activator for nuclear factor κB ligand/ receptor activator for nuclear factor κB (RANKL/RANK) pathway is critical for RANK-expressing cancer cells to home to bones, and c-Src is critical for cancer progression. The objective of this study was to explore the effect of c-Src in the RANKL/RANK pathway and migration activity in human breast cancer cells. Breast cancer cell lines MCF-7, MDA-MB-231 and BT-474 were obtained and cultured. Flow cytometry was used to examine RANK expression. The results showed that RANK was expressed in breast cancer cell lines MCF-7, MDA-MB-231 and BT-474, and soluble RANKL (sRANKL)-triggered migration of breast cancer cells by activating ERK1/2, Akt and c-Src. The sRANKL-induced migration was blocked with RANKL inhibitor osteoprotegerin (OPG), MEK inhibitor PD98059, PI3K inhibitor LY294002 and Src inhibitor PP2. Inhibition of c-Src function with PP2 blocked the activation of Akt and ERK1/2, resulting in the inhibition of RANKL-induced migration. In conclusion, RANKL was found to increase the migration of breast cancer cells by activating the c-Src-Akt and c-Src-ERK signaling pathways.

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Suppression of EGF‐induced tumor cell migration and matrix metalloproteinase‐9 expression by capsaicin via the inhibition of EGFR‐mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP‐1 signaling

Cited by 100 publications

References 37 publications

Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function

N-cadherin expression is regulated by UTP in schwannoma cells

C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway

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