Caretta Antonio, Denaro Luca, D'Avella Domenico, Mucignat-Caretta Carla
Department of Food and Drug, University of Parma, 43100 Parma, Italy.
National Institute of Biostructures and Biosystems, 00136 Roma, Italy.
Cancers (Basel). 2019 Oct 29;11(11):1686. doi: 10.3390/cancers11111686.
Deregulation of intracellular signal transduction pathways is a hallmark of cancer cells, clearly differentiating them from healthy cells. Differential intracellular distribution of the cAMP-dependent protein kinases (PKA) was previously detected in cell cultures and in vivo in glioblastoma and medulloblastoma. Our goal is to extend this observation to meningioma, to explore possible differences among tumors of different origins and prospective outcomes. The distribution of regulatory and catalytic subunits of PKA has been examined in tissue specimens obtained during surgery from meningioma patients. PKA RI subunit appeared more evenly distributed throughout the cytoplasm, but it was clearly detectable only in some tumors. RII was present in discrete spots, presumably at high local concentration; these aggregates could also be visualized under equilibrium binding conditions with fluorescent 8-substituted cAMP analogues, at variance with normal brain tissue and other brain tumors. The PKA catalytic subunit showed exactly overlapping pattern to RII and in fixed sections could be visualized by fluorescent cAMP analogues. Gene expression analysis showed that the PKA catalytic subunit revealed a significant correlation pattern with genes involved in meningioma. Hence, meningioma patients show a distinctive distribution pattern of PKA regulatory and catalytic subunits, different from glioblastoma, medulloblastoma, and healthy brain tissue. These observations raise the possibility of exploiting the PKA intracellular pathway as a diagnostic tool and possible therapeutic interventions.
细胞内信号转导通路失调是癌细胞的一个标志，这使其与健康细胞明显区分开来。先前在细胞培养以及胶质母细胞瘤和髓母细胞瘤的体内实验中检测到了环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）在细胞内的不同分布。我们的目标是将这一观察结果扩展到脑膜瘤，以探索不同起源肿瘤之间可能存在的差异以及预期结果。我们已经在脑膜瘤患者手术过程中获取的组织标本中检测了PKA调节亚基和催化亚基的分布。PKA RI亚基在整个细胞质中的分布似乎更为均匀，但仅在一些肿瘤中可明显检测到。RII呈离散斑点状存在，推测处于高局部浓度；与正常脑组织和其他脑肿瘤不同，在与荧光8-取代cAMP类似物的平衡结合条件下也可观察到这些聚集体。PKA催化亚基与RII呈现完全重叠的模式，在固定切片中可用荧光cAMP类似物观察到。基因表达分析表明，PKA催化亚基与脑膜瘤相关基因呈现出显著的相关模式。因此，脑膜瘤患者表现出与胶质母细胞瘤、髓母细胞瘤和健康脑组织不同的PKA调节亚基和催化亚基分布模式。这些观察结果增加了将PKA细胞内途径用作诊断工具和可能的治疗干预手段的可能性。
