Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue

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

doi:10.3390/cancers10010002

Cited by 6 publications

(16 citation statements)

References 46 publications

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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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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

Self Cite

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“…Another strategy could be to block the phosphodiesterase PDE4 by Rolipram or other inhibitors of this enzyme. PDE4, which specifically hydrolyzes cAMP, is often overexpressed in cancer cells [43,44,45,46,47,48].…”

Section: Discussionmentioning

confidence: 99%

“…Decreased activation of the cAMP-dependent pathway and lower levels of cAMP are generally associated with increased tumor grade and decreased overall patient survival. An extensive and converging documentation supports the potent tumor suppressor function of the cAMP/PKA axis in GBM and MB cells [43,44,45,46,47,48].…”

Section: Introductionmentioning

confidence: 99%

PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP

Bensalma

Turpault

Balandre

et al. 2019

Cancers

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Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the “VIP-receptor system”, has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP10-28 increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP10-28 increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP10-28 effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process.

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“…As shown in figure 6A, a dephosphorylation of GSK3/ was observed at 24hpi, while GSK3/ protein levels tend to be reduced at 48hpi. Although targeting of PKA and GSK-3 activity may result in glioma conventional cell death (40)(41)(42), PKA inhibition and GSK-3 down-regulation could also contribute to Delta-24-RGD-induced autophagic flux in glioma cells (27,43). were significantly increased in a time-dependent manner ( Figure 7A).…”

Section: Activation State Of Predictive Interactome Hubs Upon Delta-2mentioning

confidence: 99%

Oncolytic adenovirus Delta-24-RGD induces a widespread glioma proteotype remodeling during autophagy

González-Morales

Zabaleta

García-Moure

et al. 2019

Journal of Proteomics

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Adenovirus Delta-24-RGD has shown a remarkable efficacy in a phase I clinical trial for glioblastoma. Delta-24-RGD induces autophagy in glioma cells, however, the molecular derangements associated with Delta-24-RGD infection remains poorly understood. Here, proteomics was applied to characterize the glioma metabolic disturbances soon after Delta-24-RGD internalization and late in infection. Minutes post-infection, a rapid survival reprogramming of glioma cells was evidenced by an early c-Jun activation and a time-dependent dephosphorylation of multiple survival kinases. At 48 hours postinfection (hpi), a severe intracellular proteostasis impairment was characterized, detecting differentially expressed proteins related to mRNA splicing, cytoskeletal organization, oxidative response, and inflammation. Specific kinase-regulated protein interactomes for Delta-24-RGD-modulated proteome revealed interferences with the activation dynamics of protein kinases C and A (PKC, PKA), tyrosine-protein kinase Src (c-Src), glycogen synthase kinase-3 (GSK-3) as well as serine/threonine-protein phosphatases 1 and 2A (PP1, PP2A) at 48hpi, in parallel with adenoviral protein overproduction. Moreover, the late activation of the nuclear factor kappa B (NF-κB) correlates with the extracellular increment of specific cytokines involved in migration, and activation of different inflammatory cells. Taken together, our integrative analysis provides further insights into the effects triggered by Delta-24-RGD in the modulation of tumor suppression and immune response against glioma.

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Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue

Cited by 6 publications

References 46 publications

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

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

PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP

Oncolytic adenovirus Delta-24-RGD induces a widespread glioma proteotype remodeling during autophagy

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