Modification of glucocorticoid sensitivity by MAP kinase signaling pathways in glucocorticoid-induced T-cell apoptosis

Tanaka, Tomoko; Okabe, Taijiro; Gondo, Shigeki; Fukuda, Mitsue; Yamamoto, Masahiro; Umemura, Tomonari; Tani, Kenzaburo; Nomura, Masatoshi; Goto, Kiminobu; Yanase, Toshihiko; Nawata, Hajime

doi:10.1016/j.exphem.2006.06.018

Cited by 19 publications

(14 citation statements)

References 32 publications

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“…Cell-type specificity also plays a role [62]. The ability of a MEK inhibitor to sensitize lymphoid/myeloid cells to glucocorticoids, as we see in the current study, is nearly universal [6,43,60,61,63]. …”

Section: Discussionmentioning

confidence: 77%

Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells

Tome

Jaramillo

Briehl

2011

Free Radical Biology and Medicine

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Glucocorticoid-induced apoptosis is exploited clinically for the treatment of hematologic malignancies. Determining required molecular events for glucocorticoid-induced apoptosis will identify resistance mechanisms and suggest strategies for overcoming resistance. In the current study, we found that glucocorticoid treatment of WEHI7.2 murine thymic lymphoma cells increased the steady state [H2O2] and oxidized the intracellular redox environment prior to cytochrome c release. Removal of glucocorticoids after the H2O2 increase resulted in a 30% clonogenicity; treatment with PEG-CAT increased clonogenicity to 65%. Human leukemia cell lines also showed increased H2O2 in response to glucocorticoids and attenuated apoptosis after PEG-CAT treatment. WEHI7.2 cells that overexpress catalase (CAT2, CAT38) or are selected for resistance to H2O2 (200R) removed enough of the H2O2 generated by glucocorticoids to prevent oxidation of the intracellular redox environment. CAT2, CAT38 and 200R cells showed a 90–100% clonogenicity. The resistant cells maintained pERK survival signaling in response to glucocorticoids while the sensitive cells did not. Treating the resistant cells with a MEK inhibitor sensitized them to glucocorticoids. These data indicate that:1) an increase in H2O2 is necessary for glucocorticoid-induced apoptosis in lymphoid cells; 2) increased H2O2 removal causes glucocorticoid resistance; and 3) MEK inhibition can sensitize oxidative stress resistant cells to glucocorticoids.

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Section: Discussionmentioning

confidence: 77%

Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells

Tome

Jaramillo

Briehl

2011

Free Radical Biology and Medicine

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“…This suggested that combined contributions from JNK and ERK favored Dex resistance. The anti-apoptotic effect of ERK in relation to GCs in a different clone of CEM cells has recently been reported [11]. We hypothesized that the elevated levels of phospho-(JNK + ERK) were at least partly responsible for the resistance to Dex of CEM-C1-15 cells.…”

Section: Discussionmentioning

confidence: 89%

“…By use of clones from the CEM line of childhood acute lymphoblastic leukemia (ALL) cells, we have shown that the cAMP/protein kinase A (PKA) and mitogen- activated protein kinase (MAPK) signaling pathways strongly influence the response of human ALL cells to GC. These findings have recently been confirmed [11]. Activation of PKA by use of forskolin (FSK) to elevate cell cAMP levels synergizes with GC to kill inherently GC-sensitive CEM clones.…”

Section: Introductionmentioning

confidence: 87%

Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

et al. 2007

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Background: Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoidrelated apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone.

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“…pGL3-MMTV, pCMV-hAR, pRL-SV40, pGL3-hPSA-promoter, hAR-GFP, (GRE)2-tk-Luc, pcDNA-GR␣, pRL-CMV, pA3-ERE2, pSG1-ER␣, pERE2-tk109-Luc, and pSG5-ER␤ were as described previously (25)(26)(27)(28). pcDNA3-MR and pcDNA3-PR were kindly provided by Dr. Shigeaki Kato (University of Tokyo, Tokyo, Japan).…”

Section: Plasmid Constructionmentioning

confidence: 99%

A Novel Synthetic Androgen Receptor Ligand, S42, Works as a Selective Androgen Receptor Modulator and Possesses Metabolic Effects with Little Impact on the Prostate

et al. 2009

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We identified a novel synthetic steroid, S42, as a promising candidate of selective androgen receptor (AR) modulator. Results of the whole-cell binding assay using COS-7 cells exogenously expressing various steroid receptors indicated that S42 specifically binds to AR and progesterone receptor. When orchiectomized Sprague Dawley rats were administered with S42 for 3 wk, the muscle weight of the levator ani was increased as markedly as that induced by 5alpha-dihydrotestosterone (DHT), but the weight of the prostate was not elevated at any doses in contrast to DHT. The plasma concentrations of gonadotropin and adiponectin, those down-regulated by DHT, were unaffected by S42. In addition, although the plasma triglyceride level was unaffected by DHT, it was significantly reduced by S42. This effect of S42 was associated with suppression of the SRBP-1c-mediated lipogenic and insulin-desensitizing pathway in the liver and visceral fat. Taken together, S42 works as an AR agonist in muscle and as an AR antagonist in the prostate, pituitary gland, and liver, accompanying beneficial potentials on lipid metabolism.

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Modification of glucocorticoid sensitivity by MAP kinase signaling pathways in glucocorticoid-induced T-cell apoptosis

Cited by 19 publications

References 32 publications

Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells

Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells

Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

A Novel Synthetic Androgen Receptor Ligand, S42, Works as a Selective Androgen Receptor Modulator and Possesses Metabolic Effects with Little Impact on the Prostate

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