Protein kinase A regulatory subunit distribution in medulloblastoma

Mucignat‐Caretta, Carla; Denaro, Luca; Redaelli, Marco; D’Avella, Domenico; Caretta, Antonio

doi:10.1186/1471-2407-10-141

Cited by 7 publications

(9 citation statements)

References 20 publications

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“…When CXCR4 activity is blocked, and hence cAMP production increases, medulloblastoma growth is inhibited, similarly to phosphodiesterase blockade [75]. A differential distribution of PKA regulatory subunits is typical of medulloblastoma [76], and may be related to PKA role in medulloblastoma pathogenesis.…”

Section: Involvement Of Pka Regulatory Subunits In Different Cancersmentioning

confidence: 99%

Protein Kinase A in Cancer

Caretta

Mucignat‐Caretta

2011

Cancers

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In the past, many chromosomal and genetic alterations have been examined as possible causes of cancer. However, some tumors do not display a clear molecular and/or genetic signature. Therefore, other cellular processes may be involved in carcinogenesis. Genetic alterations of proteins involved in signal transduction have been extensively studied, for example oncogenes, while modifications in intracellular compartmentalization of these molecules, or changes in the expression of unmodified genes have received less attention. Yet, epigenetic modulation of second messenger systems can deeply modify cellular functioning and in the end may cause instability of many processes, including cell mitosis. It is important to understand the functional meaning of modifications in second messenger intracellular pathways and unravel the role of downstream proteins in the initiation and growth of tumors. Within this framework, the cAMP system has been examined. cAMP is a second messenger involved in regulation of a variety of cellular functions. It acts mainly through its binding to cAMP-activated protein kinases (PKA), that were suggested to participate in the onset and progression of various tumors. PKA may represent a biomarker for tumor detection, identification and staging, and may be a potential target for pharmacological treatment of tumors.

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Section: Involvement Of Pka Regulatory Subunits In Different Cancersmentioning

confidence: 99%

Protein Kinase A in Cancer

Caretta

Mucignat‐Caretta

2011

Cancers

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“…In general, monitoring the distribution of PKA subunits in the brain may be relevant because it varies in animal models of depression, [ 18 ] malignant glioma, [ 19 ] and Parkinson's disease. [ 20 ] A variety of human tumors, including medulloblastoma [ 21 ] and glioblastoma, [ 22 ] extended and validated the observations made on animals.…”

Section: Discussionmentioning

confidence: 72%

A new sensitive and subunit‐selective molecular tool for investigating protein kinase A in the brain

Ribaudo

Zagotto

Ongaro

et al. 2020

Archiv der Pharmazie

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Despite cellular complexity, a limited number of small molecules act as intracellular second messengers. Protein kinase A (PKA) is the main transducer of the information carried by cyclic adenosine monophosphate (cAMP). Recently, cellular imaging has achieved major technical advancements, although the search for more specific and sensitive low‐molecular‐weight probes to explore subcellular events involving second messengers is still in progress. The convergent synthesis of a novel, fluorescent small molecule comprising the cAMP structure and a rhodamine‐based fluorescent residue, connected through a flexible linker, is described here. The interaction motif of this compound with PKA was investigated in silico using a blind docking approach, comparing its theoretical binding energy with the one calculated for cAMP. Moreover, the predicted pharmacokinetic properties were also computed and discussed. The new probe was tested on three areas of the mouse central nervous system (parietal cerebral cortex, hippocampus, and cerebellar cortex) with different fixation methods demonstrating remarkable selectivity towards the PKA RIα subunit. The probe showed overall better performances when compared to other commercially available fluorescent cAMP analogues, acting at lower concentrations, and providing stable labeling.

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“…The most striking feature of GBM samples is however the consistent R2 immunoreactivity in the tumor cells, located at the Golgi, an association that was previously observed in different cells [ 27 ]. R2 distribution in GBM is different from medulloblastoma [ 17 ] and resembles the distribution observed in the mouse and rat glioma models [ 9 ]. This is relevant, since the expression of some proteins has been recently shown to change when culturing GBM, as compared to the tissue sample [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…As reported by other groups, we confirmed that activating the PKA system results in rodent glioma cell apoptosis [ 16 ]. Moreover, in human medulloblastoma specimens, the distribution of PKA regulatory subunits was different from that observed in glioblastoma models [ 17 ]. These observations point to PKA as a possible molecular target for tumor diagnosis and therapy [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue

Mucignat‐Caretta

Denaro

D’Avella

et al. 2017

Cancers

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Brain tumor glioblastoma has no clear molecular signature and there is no effective therapy. In rodents, the intracellular distribution of the cyclic AMP (cAMP)-dependent protein kinase (Protein kinase A, PKA) R2Alpha subunit was previously shown to differentiate tumor cells from healthy brain cells. Now, we aim to validate this observation in human tumors. The distribution of regulatory (R1 and R2) and catalytic subunits of PKA was examined via immunohistochemistry and Western blot in primary cell cultures and biopsies from 11 glioblastoma patients. Data were compared with information obtained from 17 other different tumor samples. The R1 subunit was clearly detectable only in some samples. The catalytic subunit was variably distributed in the different tumors. Similar to rodent tumors, all human glioblastoma specimens showed perinuclear R2 distribution in the Golgi area, while it was undetectable outside the tumor. To test the effect of targeting PKA as a therapeutic strategy, the intracellular cyclic AMP concentration was modulated with different agents in four human glioblastoma cell lines. A significant increase in cell death was detected after increasing cAMP levels or modulating PKA activity. These data raise the possibility of targeting the PKA intracellular pathway for the development of diagnostic and/or therapeutic tools for human glioblastoma.

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Protein kinase A regulatory subunit distribution in medulloblastoma

Cited by 7 publications

References 20 publications

Protein Kinase A in Cancer

Protein Kinase A in Cancer

A new sensitive and subunit‐selective molecular tool for investigating protein kinase A in the brain

Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue

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