Involvement of p38α Mitogen-activated Protein Kinase in Lung Metastasis of Tumor Cells

Matsuo, Yuji; Amano, Sadao; Furuya, Mitsuko; Namiki, Kana; Sakurai, Kazutoshi; Nishiyama, Mariko; Sudo, Tatsuhiko; Kuriyama, Takayuki; Kimura, Sadao; Kasuya, Yoshitoshi

doi:10.1074/jbc.m604371200

Cited by 40 publications

(30 citation statements)

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“…5). The activated c-Src-FAK complexes may then signal through the p38 MAPK/NF-B signaling pathways, leading to enhanced cell motility, invasion, and metastasis as shown in this and previous studies (4,9,31). The present findings suggest that MDA-9/syntenin and its interacting partners represent potential therapeutic targets to reduce cancer metastasis.…”

Section: Discussionsupporting

confidence: 81%

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

Boukerche

Prévot

et al. 2008

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

118

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The scaffold PDZ-domain containing protein mda-9/syntenin functions as a positive regulator of cancer cell progression in human melanoma and other tumors. mda-9/Syntenin regulates cell motility and invasion by altering defined biochemical and signaling pathways, including focal adhesion kinase (FAK), p38 mitogenactivated protein kinase (MAPK) and NF-B, but precisely how mda-9/syntenin organizes these multiprotein signaling complexes is not well understood. Using a clinically relevant human melanoma model, we demonstrate that mda-9/syntenin physically interacts with c-Src and this communication correlates with an increase in FAK/c-Src complex formation and c-Src activation. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin or addition of c-Src siRNA, suppresses melanoma cell migration, anchorage-independent growth, and spontaneous tumor cell dissemination in vivo in a human melanoma animal metastasis model. These data are compatible with a model wherein interaction of MDA-9/syntenin with c-Src promotes the formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread. These provocative findings highlight mda-9/ syntenin and its interacting partners as promising therapeutic targets for intervention of metastasis. Understanding and preventing this process and its dire consequences remain formidable obstacles in achieving successful treatment outcomes in advanced cancer patients. In the context of advanced melanoma, the response rate of patients with metastatic disease to single agent chemotherapy or combination therapies is frequently less than 10% (1). Given this bleak picture, it is vital to develop new, efficacious, and rationally designed treatment strategies to, ideally, prevent or effectively treat metastasis. In this context, defining relevant genes that are seminal regulators of metastasis provide an entry point for developing improved therapies.Melanoma differentiation associated gene-9 (mda-9) was cloned in our laboratory (2, 3) as a unique gene displaying biphasic expression during terminal differentiation of human melanoma cells treated with a combination of fibroblast IFN (IFN-␤) and the antileukemic compound mezerein (MEZ). These changes are consistent with early enhancement followed by decreased expression during the course of reversion of the cancer phenotype in melanoma cells (2, 3). mda-9, also called syntenin, expression displays an inverse relationship with tumor progression, with lowlevel expression in melanocytes and radial growth phase (RGP) primary melanoma versus elevated expression in vertical growth phase (VGP) primary melanoma and metastatic melanomas (4, 5). The level of mda-9/syntenin is also elevated in multiple additional cancers, including breast and gastric carcinomas, suggesting an expanded involvement in tumor progression (6). Recently, we confirmed the importance of mda-9/syntenin in metastasis in vivo, providing direct support for mda-9/syntenin as an essential gene controlling melanoma progres...

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Section: Discussionsupporting

confidence: 81%

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

Boukerche

Prévot

et al. 2008

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

118

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“…Therefore, the p38␣ activity level may affect the commitment of ESCs to develop into different cell lineages. In another study, Matsuo et al (2006) reported that that the rate of metastasis of lung tumor cells injected into p38␣ ϩ/Ϫ mice was markedly decreased compared to that in wild-type mice. Further analysis revealed that the p38␣ ϩ/Ϫ mice have a lower expression of E-and P-selectin and a reduced interaction between tumor cells and ECs.…”

Section: Discussionmentioning

confidence: 98%

p38α MAP kinase‐deficient mouse embryonic stem cells can differentiate to endothelial cells, smooth muscle cells, and neurons

Guo

Huang

2007

Developmental Dynamics

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“…Of interest, in human umbilical vein endothelial cells (HUVECs) expression of dominant negative forms of p38alpha and p38gamma as well as its downstream kinase MK2, but not p38beta or p38delta, blocks VEGF (vascular endothelial growth factor) induced endothelial migration (117). However, a recent study showed a resistance of p38alpha +/− mice to experimental lung metastasis as compared to the normal mice following an intravenous injection of mouse melanoma F10 and Lewis lung carcinoma cells (118). These results indicate that p38alpha activity in tumor versus host may play an opposite role in regulating tumor invasion and metastasis.…”

Section: The Roles Of the P38 Pathway In Regulating Cell Invasion Andmentioning

confidence: 99%

The p38 MAPK stress pathway as a tumor suppressor or more?

Loesch¹

2008

Front Biosci

100

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Abstractp38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies. KeywordsThe p38 MAPK pathway; Ras; Tumor Suppressor; isoform-specific; Oncogenesis; Review INTRODUCTIONMAPKs (mitogen-activated protein kinases) consist of ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 cascades (1, 2). Classically, MAPKs function by phosphorylating substrates containing consensus sequence Ser/Thr-Pro (3) after they are phosphorylated and activated by upstream kinases (MAPK kinases). Each of these MAPK pathways has several family members but all share the same conservative Thr-XaaTyr phosphorylation motif (where Xaa is any amino-acid) (1, 2, 4). The ERK activity is mostly frequently activated by mitogens and required for cell proliferation, differentiation and/or transformation (5, 6). JNK and p38 pathways, on the other hand, are predominantly responsive to stress and cytokine signaling and play an in important role in regulating stress response and inflammation (7,8). MAPKs can be activated almost by all type of stimuli and are consequently involved in many critical biological processes such as proliferation, differentiation, cell death and transformation through regulating downstream gene expression and/or interacting with other signaling cascades.Send correspondence to: Dr. Guan Chen, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, gchen@mcw.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe p38 upstream activators include MAPK kinase 6 (MKK6) and MKK3. Downstream effectors consist of kinases such as MK2 (MAPK-activating protein kinase 2) and PRAK (p38-related/activated protein kinase) as well as transcription factors including ATF-2 (activating transcription factor-2), MEF2 (myocyte enhancement factor 2), and c-Jun (4, 9). The mammalian p38 family consists of four isoform proteins (alpha, beta, gamma, and delta), with p38alpha and p38beta 75% identical in their amino-acid sequence, and p38gamma and p38delta about 60% identical to p38alpha (4, 10). p38alpha and p38beta are susceptible to inhibition by SB drugs (SB203580 and SB202190) wh...

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Involvement of p38α Mitogen-activated Protein Kinase in Lung Metastasis of Tumor Cells

Cited by 40 publications

References 39 publications

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

p38α MAP kinase‐deficient mouse embryonic stem cells can differentiate to endothelial cells, smooth muscle cells, and neurons

The p38 MAPK stress pathway as a tumor suppressor or more?

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