Dichotomous role of protein kinase A type I (PKAI) in the tumor microenvironment: A potential target for ‘two-in-one’ cancer chemoimmunotherapeutics

Hussain, Muzammal; Tang, Fei; Liu, Jinsong; Zhang, Jiancun; Javeed, Aqeel

doi:10.1016/j.canlet.2015.07.047

Cited by 13 publications

(8 citation statements)

References 107 publications

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“…PKA associated NF-κB activation has been directly linked to a poor prognosis in oral cancer, and inhibition of PKA was shown to inhibit tumor cell proliferation, induce cell death, and modulate a number of pro-inflammatory and angiogenic genes associated with NF-κB activation [66,67]. PKA has also been shown to play a role in the suppression of anti-tumor immune surveillance of the host [68], making it a particularly attractive target for chemoprevention. Previous studies have demonstrated inhibition of NF-κB by BRB phytochemicals and this inhibition is associated with a reduction in oral carcinogenesis [6,7,11,69].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention

et al. 2019

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Oral cancer is a public health problem with an incidence of almost 50,000 and a mortality of 10,000 each year in the USA alone. Black raspberries (BRBs) have been shown to inhibit oral carcinogenesis in several preclinical models, but our understanding of how BRB phytochemicals affect the metabolic pathways during oral carcinogenesis remains incomplete. We used a well-established rat oral cancer model to determine potential metabolic pathways impacted by BRBs during oral carcinogenesis. F344 rats were exposed to the oral carcinogen 4-nitroquinoline-1-oxide in drinking water for 14 weeks, then regular drinking water for six weeks. Carcinogen exposed rats were fed a 5% or 10% BRB supplemented diet or control diet for six weeks after carcinogen exposure. RNA-Seq transcriptome analysis on rat tongue, and mass spectrometry and NMR metabolomics analysis on rat urine were performed. We tentatively identified 57 differentially or uniquely expressed metabolites and over 662 modulated genes in rats being fed with BRB. Glycolysis and AMPK pathways were modulated during BRB-mediated oral cancer chemoprevention. Glycolytic enzymes Aldoa, Hk2, Tpi1, Pgam2, Pfkl, and Pkm2 as well as the PKA-AMPK pathway genes Prkaa2, Pde4a, Pde10a, Ywhag, and Crebbp were downregulated by BRBs during oral cancer chemoprevention. Furthermore, the glycolysis metabolite glucose-6-phosphate decreased in BRB-administered rats. Our data reveal the novel metabolic pathways modulated by BRB phytochemicals that can be targeted during the chemoprevention of oral cancer.

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Section: Discussionmentioning

confidence: 99%

Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention

et al. 2019

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“…A variety of physiological responses are regulated by these effector molecules, including energy metabolism, expression of genes, cellular proliferation and death 9 . Hence, various alterations in the activity of cAMP signaling was reported in many diseases, including cancer, and therefore cAMP signaling might be a potential target to develop novel treatments for many diseases 10,11 . cAMP signaling was reported to affect some DNA damage repair mechanisms, including base excision repair (BER) 12,13 and nucleotide excision repair (NER) 14 .…”

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confidence: 99%

Inhibition of non-homologous end joining of gamma ray-induced DNA double-strand breaks by cAMP signaling in lung cancer cells

Noh

Juhnn

2020

Sci Rep

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DnA double-strand breaks (DSB) are formed by various exogenous and endogenous factors and are repaired by homologous recombination and non-homologous end joining (nHeJ). DnA-dependent protein kinase (DnA-pK) is the principal enzyme for nHeJ. We explored the role and the underlying mechanism of cAMp signaling in the nHeJ repair of DSBs resulted from gamma ray irradiation to nonsmall cell lung cancer (nSLc) cells. Activated cAMp signaling by expression of an activated stimulatory GTP-binding protein or by pretreatment with isoproterenol and prostaglandin E2, delayed the repair of DSBs resulted from gamma ray irradiation, and the delaying effects depended on protein kinase A (PKA). Activated cAMP signaling suppressed XRCC4 and DNA ligase IV recruitment into DSB foci, and reduced phosphorylation at T2609 in DNA-PK catalytic subunit (DNA-PKcs) with a concomitant increase in phosphorylation at S2056 in PKA-dependent ways following gamma ray irradiation. cAMP signaling decreased phosphorylation of T2609 by protein phosphatase 2A-dependent inhibition of AtM. We conclude that cAMp signaling delays the repair of gamma ray-induced DnA DSBs in NSLC cells by inhibiting NHEJ via PKA-dependent pathways, and that cAMP signaling differentially modulates DNA-PKcs phosphorylation at S2056 and T2609, which might contribute to the inhibition of nHeJ in nSLc cells. DNA double-strand breaks (DSBs) are localized chromosomal injuries bearing breaks at two DNA strands. They can be produced by various exogenous factors such as chemical mutagens, anticancer chemotherapeutic drugs and high-energy radiation, and by endogenous processes including DNA replication and recombination of V(D) J immunoglobulin genes 1-3. DSBs are harmful lesions that, when they are not repaired or not properly repaired, can result in chromosomal mutations, apoptosis, aging, and diseases including neurodegeneration and cancer 4-6. Homologous recombination (HR) and non-homologous end-joining (NHEJ) are the major mechanisms for DSB repair in vertebrates. HR requires a homologous DNA molecule as a template to recover any lost sequence information at the break sites and is therefore free of errors. HR, thus, preferentially repairs DNA in G2 and late S phase of the cell cycle. NHEJ restores DNA integrity by linking the two broken ends without using extensive sequence homology, and is activated during the whole cell cycle 7. NHEJ repair often results in small deletions and insertions at the repaired site. More than two NHEJ subtypes operate in many cells including classical NHEJ and alternative NHEJ. Classical NHEJ can be broken down into several stages, such as synapse, end-processing, ligation and complex dissociation, and it requires numerous enzymes, namely, DNA-dependent protein kinase (DNA-PK), nucleases, DNA polymerases, and ligases. DNA-PK is a nuclear serine/threonine kinase, and exists as complex of a catalytic subunit (DNA-PKcs) and a regulatory heterodimeric Ku complex (Ku70/Ku80) 1. DNA-PK is one of the core molecules essential to NHEJ, and known to phosphoryl...

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“…It has long been recognized that PKA is 10 times more abundant in GBM than in the normal brain [ 22 ], that glioma cells contain protein kinase A type 2, and that after cAMP stimulation, the catalytic subunits redistribute to particulate fractions [ 23 ]. Moreover, PKA imbalance has been linked to tumorigenesis [ 24 ]. We showed in murine GBM models that the PKA R2 subunit is concentrated in the Golgi area, and that interference with PKA activity may lead mice glioblastoma cells to apoptotic death [ 15 ].…”

Section: Discussionmentioning

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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Dichotomous role of protein kinase A type I (PKAI) in the tumor microenvironment: A potential target for ‘two-in-one’ cancer chemoimmunotherapeutics

Cited by 13 publications

References 107 publications

Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention

Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention

Inhibition of non-homologous end joining of gamma ray-induced DNA double-strand breaks by cAMP signaling in lung cancer cells

Protein Kinase A Distribution Differentiates Human Glioblastoma from Brain Tissue

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