Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway

Abstract

Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentration can control both structure and activity of cN-II. In this paper, using a capillary electrophoresis technique, we demonstrated that a partial silencing of cN-II in a pulmonary carcinoma cell line (NCI-H292) is accompanied by a decrease in adenylate pool, without affecting the energy charge. We also found that cN-II silencing decreased proliferation and increased oxidative metabolism, as indicated by the decreased production of lactate. These effects, as demonstrated by Western blotting, appear to be mediated by both p53 and AMP-activated protein kinase, as most of them are prevented by pifithrin-α, a known p53 inhibitor. These results are in line with our previous observations of a shift towards a more oxidative and less proliferative phenotype of tumoral cells with a low expression of cN-II, thus supporting the search for specific inhibitors of this enzyme as a therapeutic tool for the treatment of tumors.

Comprehensive analysis of NT5DC family prognostic and immune significance in breast cancer

“…[ 5 ] In recent years, cancer susceptibility and development are associated with NT5DC family members. The expression of NT5C2 plays an important role in lung cancer, [ 10 ] acute leukemia, [ 35 ] and astrocytoma. [ 36 ] In breast cancer, by regulating ROS metabolism and defense, NT5C2 regulates cellular responses to glucose deprivation.…”

“…[7][8][9] In lung tumor cells, the silence of NT5C2 opposes the cancer phenotype, activates the p53/AMPK pathway and regulates metabolism. [10,11] Raza et al [12] showed that NT5C2 deficiency facilitates tumor growth, response to chemotherapeutic and migration. When treating non-small cell lung cancer cells with gemcitabine and platinum, the expression of NT5C2 can be used as an indicator of response.…”

Comprehensive Analysis of Prognostic Value and Immune Infiltration of the NT5DC Family in Hepatocellular Carcinoma

“…It was also found that lung cancer patients with high NT5C2 expression had poor prognosis, and the reduction of NT5C2 could increase the sensitivity to gemcitabine [ 21 ]. Another study displayed that silencing NT5C2 increased oxidative metabolism and reduced lung cancer cell proliferation by activating p53 and AMPK [ 22 ]. In glioblastoma, NT5C2 could regulate tumor cell proliferation and drug sensitivity [ 23 ].…”

Inborn Errors of Purine Salvage and Catabolism

“…However, other authors report that the manipulation of cN-I is more efficient in regulating AMP intracellular concentrations and AMPK activity [ 176 ]. Recently, cN-II silencing in tumor cells of epithelial origin indicated that a total absence of cN-II expression was followed by a decrease in proliferation and motility, and the activation of AMPK and p53 [ 177 ]. So far, it has been reported that cN-II was silenced in zebrafish [ 178 ], in Drosophila [ 179 ], and in mouse [ 180 ].…”