Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways

Life Sciences ◽  
2012 ◽  
Vol 90 (9-10) ◽  
pp. 373-380 ◽  
Author(s):  
Eun-Yi Moon ◽  
Geun-Hee Lee ◽  
Myung-Shik Lee ◽  
Hwan-Mook Kim ◽  
Jae-Wook Lee
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Phosphodiesterase Inhibitors ◽  
Glioblastoma Cell ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cell ◽  
Kinase A

scholarly journals Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue

Cancers ◽  
2017 ◽  
Vol 10 (1) ◽  
pp. 2 ◽  
Author(s):  
Carla Mucignat-Caretta ◽  
Luca Denaro ◽  
Domenico D’Avella ◽  
Antonio Caretta
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Brain Tissue ◽  
Human Glioblastoma ◽  
Kinase A

Rexinoid-Triggered Differentiation and Tumor-Selective Apoptosis of AML by Protein Kinase A-Mediated De-Subordination.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2235-2235
Author(s):  
Ettore Mariano Schiavone ◽  
Lucia Altucci ◽  
Mariacarla De Simone ◽  
Felicetto Ferrara ◽  
Aurélie Rossin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
Hdac Inhibitors ◽  
Death Receptor ◽  
Phosphodiesterase Inhibitors ◽  
Camp Phosphodiesterase ◽  
Tumor Selective ◽  
Kinase A

Abstract Apart from PML-RARα acute promyelocytic leukemia all other acute myeloid leukemias (AML) are unresponsive to retinoid differentiation therapy. However, in our study we show that elevating the levels of cyclic AMP (cAMP) confers onto retinoid X receptor (RXR)-selective agonists (“rexinoids”) the ability to induce terminal granulocyte differentiation and apoptosis of all-trans retinoic acid-resistant and insensitive AML cell lines and patients’ AML blasts. Protein kinase A activation leads to co-repressor release from the RAR subunit of the RAR-RXR heterodimer, resulting in “de-subordination” of otherwise silent RXR, which acquires transcriptional competence in response to cognate ligands. Rexinoid-cAMP induction of endogenous RARβ is blunted in mouse embryo fibroblasts lacking RARs, but re-introduction of exogenous RARα re-establishes responsiveness, thus confirming that the RARα-RXR heterodimer is the rexinoid mediator. The apoptogenic effect of this treatment involves enhanced expression of the death receptor DR5 and its cognate ligand, the tumor necrosis factor-related apoptosis inducing ligand (TRAIL), both of which are known to induce apoptosis in a tumor cell-selective manner and lead to the activation of initiator caspases. Immunohistochemistry confirmed induction of TRAIL and DR5 in AML patient blasts cultured “ex vivo”. AML patients’ blasts responded to rexinoid-cAMP combination treatment with induction of maturation and apoptosis, independent of karyotype, immunophenotype, and FAB classification. Clonogenic assays revealed complete inhibition of blast clonogenicity in four out of five tested samples. Indeed, it is known that cAMP levels can be elevated also by treating cells with 3′, 5′-cAMP phosphodiesterase inhibitors (PDEi’s). These observation and the clinical availability of the corresponding drugs provide a rationale for initiating clinical studies addressing the efficacy of combinatorial PDEi-rexinoid therapy in AML patients. Together with our recent finding that a very promising class of epigenetic anti-tumor drugs operates through activation of TRAIL expression (Nat Med2005, 11(1):7784), the possibility to target both the ligand (TRAIL) by HDAC inhibitors and the cognate receptors (DR4, DR5) by the above described rexinoid crosstalk may represent a promising therapeutic option which might lead, despite the genetic, morphologic, and clinical variability of AML, to a novel therapeutic option for AML patients by inducing a tumor-selective death pathway.

scholarly journals Procaspase 3/p21 complex formation to resist Fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A

2000 ◽  
Vol 7 (8) ◽  
pp. 721-728 ◽  
Author(s):  
A Suzuki ◽  
H Kawano ◽  
M Hayashida ◽  
Y Hayasaki ◽  
Y Tsutomi ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Complex Formation ◽  
Protein Kinase A ◽  
Kinase A

Gastrin inhibits motility, decreases cell death levels and increases proliferation in human glioblastoma cell lines

1998 ◽  
Vol 37 (3) ◽  
pp. 373-382 ◽  
Author(s):  
Christophe De Hauwer ◽  
Isabelle Camby ◽  
Francis Darro ◽  
Isabelle Migeotte ◽  
Christine Decaestecker ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Glioblastoma Cell ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cell ◽  
Glioblastoma Cell Lines
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