PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells

Lentzsch, Suzanne; Chatterjee, Manik; Gries, Margarete; Bommert, Kurt; Gollasch, Hella; Dörken, Bernd; Bargou, Ralf C.

doi:10.1038/sj.leu.2403486

Cited by 109 publications

(89 citation statements)

References 47 publications

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“…In this context, additional potential signalling molecule for analysis is LIF. This cytokine is abundantly produced during nemosis and was originally identified as a growth inhibitor with a positive effect on differentiation of leukemic cells [34]. At the present level of analysis we are not able to denote a signal molecule produced by nemotic fibroblasts which is principally causing dormant status of the RPMI 8226 cells.…”

Section: Discussionmentioning

confidence: 60%

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

K¹,

I²,

Mistrík³

et al. 2015

neo

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Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs) predominantly in the bone marrow but tumor cells appear in the circulation in significant numbers as the disease progress. The occurrence of circulating multiple myeloma cells raises question concerning interactions between these cells and stroma of peripheral organs specifically under certain pathophysiological conditions, e.g., inflammation. Therefore, in the present study we exposed three human multiple myeloma cell lines to sterile inflammation produced in a culture dish by clusters of cell-cell contact-activated dermal fibroblasts. We now observed that myeloma cells responded differently to this particular type of stromal cell activation, nemosis. Two cell lines U-266 and LP-1 were minimally affected by the proinflammatory signalling, while the third cell line RPMI 8226 responded with growth arrest and altered expression of three phenotypic markers CD38, CD45, and CD138, indicating dedifferentiation shift of these cells to less mature PC-like phenotype. In a preliminary study we identified a subclone of cells having similar phenotype in 14 out of 23 analysed specimens of MM patients. This set of data indicates that the observed phenomenon might be clinically relevant. Our results emphasize the potential role of activated stromal fibroblasts and subsequent inflammation in altering phenotype of PCs and directing myeloma progression towards dormancy. Given the significant implication of dormant myeloma cells that might serve as a major cellular basis for the relapse, understanding their unique biology and precise elucidation of the underlying molecular mechanisms for the maintenance of quiescence is important. Therefore, we consider this study as a particular contribution to development of experimental model for in vitro studies of cancer dormancy.

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Section: Discussionmentioning

confidence: 60%

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

K¹,

I²,

Mistrík³

et al. 2015

neo

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“…Low levels of activated Akt are observed in human RCC cells (20). Some important factors, including EGF, VEGF, and TGF-b, are involved in the tumorigenesis of human carcinoma through activation of PI3K/Akt signaling cascade (38)(39)(40). These growth factors derived from RCC may be responsible for the constitutive activation of Akt.…”

Section: Discussionmentioning

confidence: 99%

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Tang

Chuang

et al. 2012

Molecular Cancer Research

107

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TNF-a is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-a production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-a are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-a induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-a treatment inhibited glycogen synthase kinase 3b (GSK-3b) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3b and suppressed the TNFa-induced EMT of RCC cells. Inactivation of GSK-3b by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3b by transduction of constitutively active GSK-3b into RCC cells suppressed TNFa-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3b, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3b activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3b plays a pivotal role in the TNF-a-mediated tumorigenesis of RCC. Mol Cancer Res; 10(8); 1109-19. Ó2012 AACR. IntroductionRenal cell carcinoma (RCC) is the tenth most common cause of cancer-related deaths worldwide (1). Although surgery is often curative, 30% of patients will present with metastases at the time of initial diagnosis (1). The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2, 3). Previous studies indicated immunotherapy is relatively effective against RCC (2, 3). However, the response rate is only 15% to 20% (1-3). Therefore, defining the factors involved in disease progression and metastasis will provide novel molecular targets for the development of effective therapies.

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“…Numerous survival-related factors secreted by HUCB cells have been shown to induce Akt activation, including glial cellderived neurotrophic factor, brain derived neurotrophic factor, leukemia inhibitory factor, IL-1␤, IL-6, insulin like growth factor 1, VEGF, and tissue inhibitor of metalloproteinases metallopeptidase inhibitor 1 (7,8,(25)(26)(27)(28). The pro-survival actions of Akt are well known.…”

Section: Discussionmentioning

confidence: 99%

Human Umbilical Cord Blood Cells Protect Oligodendrocytes from Brain Ischemia through Akt Signal Transduction

Rowe

Leonardo

Recio

et al. 2012

Journal of Biological Chemistry

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Background: Human umbilical cord blood cells are an effective experimental treatment for stroke. Results: These cells activate Akt to increase peroxiredoxin 4 and are essential for oligodendrocyte survival during ischemia. Conclusion: Akt and peroxiredoxin 4 are key molecules in transducing the cellular protection elicited by cord blood cells. Significance: Identifying this signaling pathway provides new pharmaceutical targets for stroke treatment.

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PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells

Cited by 109 publications

References 47 publications

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Human Umbilical Cord Blood Cells Protect Oligodendrocytes from Brain Ischemia through Akt Signal Transduction

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