Inhibition of PI3-kinase–Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line

Nuutinen, Ulla; Postila, Ville; Mättö, Mikko; Eeva, Jonna; Ropponen, Antti; Eray, Mine; Riikonen, Pekka; Pelkonen, Jukka

doi:10.1016/j.yexcr.2005.10.023

Cited by 21 publications

(26 citation statements)

References 38 publications

(31 reference statements)

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“…Leis et al (2004) reported that GR inhibited PI3K and Akt activity, which constituted a major mechanism underlying the antitumor effect of GC in skin. Reports also showed that GC/GR induces apoptosis in proliferative chondrocytes and a human follicular lymphoma cell line through suppression of the Akt-PI3K signaling pathway (Chrysis et al 2005, Nuutinen et al 2006. In this study, we also found that except for the down-regulation of Rhob, the activity of Akt was enhanced in RAW-GR(K) cells.…”

Section: Discussionsupporting

confidence: 75%

“…We also analyzed a 5 kb fragment of the promoter sequence upstream of the transcriptional start site of the Rhob gene, and found no consensus GRE (Chen et al 2006). In recent years, evidence has emerged that besides its role in directly regulating gene expression, GR could modulate the activity of several cytoplasmic protein kinases, such as Akt (Leis et al 2004, Chrysis et al 2005, Nuutinen et al 2006, MAPK3/1, and MAPK14 (Miller et al 2005, Qin et al 2005, to play its important roles in regulating cell proliferation, differentiation, and apoptosis. Leis et al (2004) reported that GR inhibited PI3K and Akt activity, which constituted a major mechanism underlying the antitumor effect of GC in skin.…”

Section: Discussionmentioning

confidence: 95%

“…In recent years, evidence has emerged that GR plays important roles in regulating cell proliferation by modulating the activity of Akt (Leis et al 2004, Chrysis et al 2005, Nuutinen et al 2006, MAPK3/1 and MAPK14 (Miller et al 2005, Qin et al 2005), so we examined the activated status of these kinases in RAW-GR(K) and RAW264.7 cells by western blot. We failed to find a significant difference in phosphorylated MAPK3/1 or MAPK14 level between RAW-GR(K) and RAW-control cells (data not shown), but found about a 79% increase in phosphorylated Akt in RAW-GR(K) cells compared with that of RAW-control cells (Fig.…”

Section: Akt Phosphorylation But Not Mapk3/1 and Mapk14 Is Involvedmentioning

confidence: 99%

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Role of RHOB in the antiproliferative effect of glucocorticoid receptor on macrophage RAW264.7 cells

Wang

Chen²,

Wang³

et al. 2008

Journal of Endocrinology

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Although glucocorticoid (GC) has been reported to inhibit macrophage killing activity and cytokine production in response to proinflammatory stimuli, the effect of GC on macrophage proliferation is controversial. In our previous study, we found that inhibition of glucocorticoid receptor (GR) expression in murine macrophage cell line RAW264.7 cells (RAW-GR(K) cells) by RNAi significantly promoted cell proliferation. In the present study, we provide the evidence that the expression of Rhob, a member of Rho GTPases with anti-cancer character, remarkably decreased in RAW-GR(K) and RAW264.7 cells transiently transfected with GR-RNAi vector. Overexpression or constitutive activation of Rhob in RAW-GR(K) and RAW264.7 cells by transfection with wild-type Rhob expression vector (Rhob-wt) or constitutively activated Rhob plasmid (Rhob-V14) resulted in decreased proliferation of the two cell lines. Oppositely, the proliferation of RAW264.7 cells was significantly increased when the expression of Rhob by RNA interference technique or the activity of Rhob by transfection with dominant negative Rhob mutant that is defective in nucleotide binding (Rhob-N19) was inhibited. In addition, enhanced activity of Akt, but not MAPK3/1 or MAPK14, was found in RAW-GR(K) cells. Blocking the pathway of phosphatidylinositol 3-kinase (PI3K)/Akt with the specific inhibitor LY294002 decreased the proliferation and elevated RHOB protein level, indicating that PI3K/Akt signal plays its role of proliferation modulation upstream of RHOB protein. In conclusion, these results demonstrate that Rhob plays an important role in the antiproliferative effect of GR on RAW264.7 cells by GR/Akt/Rhob signaling and Rhob negatively regulates the proliferation of RAW264.7 cells.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 95%

Section: Akt Phosphorylation But Not Mapk3/1 and Mapk14 Is Involvedmentioning

confidence: 99%

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Role of RHOB in the antiproliferative effect of glucocorticoid receptor on macrophage RAW264.7 cells

Wang

Chen²,

Wang³

et al. 2008

Journal of Endocrinology

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“…This suggests that long term increases in GR␤ expression may enhance growth by suppressing PTEN leading to over stimulation of PI3-kinase and Akt. Inhibitors of the PI3-kinase pathway enhanced GC induced apoptosis in human lymphoma cells (28), which indicate a positive feedback between glucocorticoids/GR␣ and PTEN in the suppression of growth. The interplay between GR␣ and PTEN was demonstrated in T-cells extracted from human leukemia patients, which had increased PTEN expression following GC treatment (29).…”

Section: Discussionmentioning

confidence: 89%

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte

Wuescher

Marino

et al. 2014

Journal of Biological Chemistry

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Background:The glucocorticoid receptor ␤ (GR␤) is a positive regulator of growth. Results: GR␤ suppression of PTEN resulted in enhanced phosphorylation of Akt and growth. Conclusion: GR␤ enhances insulin-induced proliferation by suppressing PTEN and activating Akt1. Significance: GR␤ suppression of PTEN indicates that it has an important role in growth factor signaling and potentially cancer.

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“…How a steroid, such as dexamethasone, functions as a cytotoxic agent is unknown. However, recent evidence suggests that it may involve the phosphatidylinositol 3-kinase (PI3K)/Akt pathway because inhibition of this pathway seems to enhance the killing of a human follicular lymphoma cell line by dexamethasone (43). Consistent with this notion, prolonged treatment of MM1.S cells with 2 Amol/L PD 0332991 (48 hours) led to a modest reduction in the phosphorylation of Akt.…”

Section: Discussionmentioning

confidence: 93%

A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6

Baughn¹,

Liberto²,

et al. 2006

Cancer Research

199

141

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Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6,

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Inhibition of PI3-kinase–Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line

Cited by 21 publications

References 38 publications

Role of RHOB in the antiproliferative effect of glucocorticoid receptor on macrophage RAW264.7 cells

Role of RHOB in the antiproliferative effect of glucocorticoid receptor on macrophage RAW264.7 cells

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6

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