Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: Relationship with cell proliferation

ObjectiveThe cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes:PRKAR1A,PRKAR1B,PRKAR2A,PRKAR2B) and two catalytic subunits. InactivatingPRKAR1Amutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics.MethodsIn this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured.ResultsA subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%±4 vs 100%±19,P<0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P<0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37±0.31 vs 1.00±0.20,P<0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors.ConclusionThis loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.

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cAMP has a protein kinase A independent regulatory effect on T cell proliferation, MAP kinase activity and on mRNA levels for IL-2 and INF-gamma

Immunology Letters ◽

10.1016/s0165-2478(97)87084-8 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 65

Author(s):

B Hofmann

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Protein Kinase ◽

Map Kinase ◽

Protein Kinase A ◽

Kinase Activity ◽

T Cell Proliferation ◽

Mrna Levels ◽

Regulatory Effect ◽

Kinase A

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Protein Kinase A-Independent Inhibition of Proliferation and Induction of Apoptosis in Human Thyroid Cancer Cells by 8-Cl-Adenosine

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2331 ◽

2008 ◽

Vol 93 (3) ◽

pp. 1020-1029 ◽

Cited By ~ 15

Author(s):

Audrey J. Robinson-White ◽

Hui-Pin Hsiao ◽

Wolfgang W. Leitner ◽

Elizabeth Greene ◽

Andrew Bauer ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thyroid Cancer ◽

Protein Kinase ◽

Protein Kinase A ◽

Cancer Cells ◽

Human Thyroid ◽

Inhibition Of Proliferation ◽

Thyroid Cancer Cells ◽

Kinase A

Abstract Purpose: Protein kinase A (PKA) affects cell proliferation in many cell types and is a potential target for cancer treatment. PKA activity is stimulated by cAMP and cAMP analogs. One such substance, 8-Cl-cAMP, and its metabolite 8-Cl-adenosine (8-Cl-ADO) are known inhibitors of cancer cell proliferation; however, their mechanism of action is controversial. We have investigated the antiproliferative effects of 8-Cl-cAMP and 8-CL-ADO on human thyroid cancer cells and determined PKA’s involvement. Experimental Design: We employed proliferation and apoptosis assays and PKA activity and cell cycle analysis to understand the effect of 8-Cl-ADO and 8-Cl-cAMP on human thyroid cancer and HeLa cell lines. Results: 8-Cl-ADO inhibited proliferation of all cells, an effect that lasted for at least 4 d. Proliferation was also inhibited by 8-Cl-cAMP, but this inhibition was reduced by 3-isobutyl-1-methylxanthine; both drugs stimulated apoptosis, and 3-isobutyl-1-methylxanthine drastically reduced 8-Cl-cAMP-induced cell death. 8-Cl-ADO induced cell accumulation in G1/S or G2/M cell cycle phases and differentially altered PKA activity and subunit levels. PKA stimulation or inhibition and adenosine receptor agonists or antagonists did not significantly affect proliferation. Conclusions: 8-Cl-ADO and 8-Cl-cAMP inhibit proliferation, induce cell cycle phase accumulation, and stimulate apoptosis in thyroid cancer cells. The effect of 8-Cl-cAMP is likely due to its metabolite 8-Cl-ADO, and PKA does not appear to have direct involvement in the inhibition of proliferation by 8-Cl-ADO. 8-Cl-ADO may be a useful therapeutic agent to be explored in aggressive thyroid cancer.

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Pinoresinol promotes MC3T3‑E1 cell proliferation and differentiation via the cyclic AMP/protein kinase�A signaling pathway

Molecular Medicine Reports ◽

10.3892/mmr.2019.10468 ◽

2019 ◽

Cited By ~ 1

Author(s):

Xin Jiang ◽

Wenjing Chen ◽

Fuguo Shen ◽

Wenlong Xiao ◽

Hongliang Guo ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Cyclic Amp ◽

Protein Kinase A ◽

Signaling Pathway ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Kinase A

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Membrane-Bound Protein Kinase A Inhibits Smooth Muscle Cell Proliferation In Vitro and In Vivo by Amplifying cAMP–Protein Kinase A Signals

Circulation Research ◽

10.1161/01.res.88.3.319 ◽

2001 ◽

Vol 88 (3) ◽

pp. 319-324 ◽

Cited By ~ 35

Author(s):

Ciro Indolfi ◽

Eugenio Stabile ◽

Carmela Coppola ◽

Adriana Gallo ◽

Cinzia Perrino ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Protein Kinase ◽

Smooth Muscle Cell ◽

Protein Kinase A ◽

Membrane Bound ◽

Proliferation In Vitro ◽

Kinase A

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Expression of p27Kip1 in Osteoblast-Like Cells during Differentiation with Parathyroid Hormone*

Endocrinology ◽

10.1210/endo.138.5.5146 ◽

1997 ◽

Vol 138 (5) ◽

pp. 1995-2004 ◽

Cited By ~ 36

Author(s):

Takehisa Onishi ◽

Keith Hruska

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Protein Kinase ◽

Protein Kinase A ◽

Osteogenic Sarcoma ◽

S Phase ◽

G1 Phase ◽

Osteoblastic Cell ◽

Cyclin Dependent Kinases ◽

Kinase A

Abstract PTH is a major systemic regulator of bone metabolism and plays an important role in both bone formation and resorption. PTH either inhibits or stimulates osteoblastic cell proliferation depending on the model that is studied. We analyzed the cell cycle of the UMR-106 cell line, a relatively differentiated osteoblastic osteogenic sarcoma line in which PTH is known to inhibit proliferation but the mechanism of action is unknown. PTH decreased the proportion of cells in S phase and increased the number of G1 phase cells. We examined the effect of PTH on the regulators of the G1 phase cyclin-dependent kinases and found that PTH increased p27Kip1, but not p21Cip1, levels. This effect was mimicked by 8-bromo-cAMP, but not by phorbol 12-myristate 13-acetate. The protein kinase A inhibitor KT5720 abolished the effect of PTH on the increase in p27Kip1 expression. PTH increased CDK2-associated p27Kip1 without affecting the levels of CDK2. CDK2 activity was down-regulated by both PTH and 8-bromo-cAMP treatment. These data suggest that PTH blocks entry of cells into S phase and inhibits cell proliferation as the consequence of an increase in p27Kip1, which is mediated through the protein kinase A pathway. The inhibition of G1 cyclin-dependent kinases by p27Kip1 could cause a reduction of phosphorylation of key substrates and inactivation of transcription factors essential for entry into S phase. The inhibition of cell cycle progression through PKA-mediated p27Kip1 induction might play an important role in PTH-induced differentiation of osteoblasts.

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