2102Ep embryonal carcinoma cells have compromised respiration and shifted bioenergetic profile distinct from H9 human embryonic stem cells

Abstract

Recent studies have shown that cellular bioenergetics may be involved in stem cell differentiation. Considering that during cancerogenesis cells acquire numerous properties of stem cells, it is possible to assume that the energy metabolism in tumorigenic cells might be differently regulated. The aim of this study was to compare the mitochondrial bioenergetic profile of normal pluripotent human embryonic stem cells (hESC) and relatively nullipotent embryonal carcinoma cells (2102Ep cell line). We examined three parameters related to cellular bioenergetics: phosphotransfer system, aerobic glycolysis, and oxygen consumption. Activities and expression levels of main enzymes that facilitate energy transfer were measured. The oxygen consumption rate studies were performed to investigate the respiratory capacity of cells. 2102Ep cells showed a shift in energy distribution towards adenylate kinase network. The total AK activity was almost 3 times higher in 2102Ep cells compared to hESCs (179.85±5.73 vs 64.39±2.55mU/mg of protein) and the expression of AK2 was significantly higher in these cells, while CK was downregulated. 2102Ep cells displayed reduced levels of oxygen consumption and increased levels of aerobic glycolysis compared to hESCs. The compromised respiration of 2102Ep cells is not the result of increased mitochondrial mass, increased proton leak, and reduced respiratory reserve capacity of the cells or impairment of respiratory chain complexes. Our data showed that the bioenergetic profile of 2102Ep cells clearly distinguishes them from normal hESCs. This should be considered when this cell line is used as a reference, and highlight the importance of further research concerning energy metabolism of stem cells.

Adenylate Kinase and Metabolic Signaling in Cancer Cells

“…AK2 and CKmit provide nucleotide exchange and metabolic signaling capacity, allowing mitochondria to export ATP and reception of cytosolic feedback signals such as ADP, AMP, and creatine (22,23,37). Phosphotransfer enzymes CK and AK have been implicated in cancer cell proliferation (35,36). In general, CK is involved in cancerous transformation, as CKB (brain-type CK) is upregulated in a variety of cancers to support growing energy needs (38).…”

“…However, in other cancer types, the downregulation of CKB and rewiring of metabolism may play an important role in colon cancer progression (40). Moreover, several studies have demonstrated that in colorectal cancer (41), breast cancer (42), neuroblastoma (35), prostate cancer (43), and sarcoma (36,44), the CKmit was downregulated. The reduction of CKmit in cancer cells was associated with the upregulation of adenylate kinase AK2 isoform in intermembrane space (36,41,42,45,46) (see Table 1).…”

“…Moreover, several studies have demonstrated that in colorectal cancer (41), breast cancer (42), neuroblastoma (35), prostate cancer (43), and sarcoma (36,44), the CKmit was downregulated. The reduction of CKmit in cancer cells was associated with the upregulation of adenylate kinase AK2 isoform in intermembrane space (36,41,42,45,46) (see Table 1). There is evidence that the expression of AK2 on the cell surface could facilitate nucleotide signaling and metastatic potential (60).…”

“…The association of HK2 with mitochondria and expression of pyruvate kinase PKM2 could promote effective yet uncontrolled energy distribution in cancer cells (27,33,34). Phosphotransfer enzymes such as CK and AK have been implicated in cancer cell proliferation (35,36). However, it is not clear whether the redistribution of phosphotransfer enzymes, especially those which are localized in mitochondria, occurs during cancer formation.…”

Adenylate Kinase: A Ubiquitous Enzyme Correlated with Medical Conditions

“…It is well known that malignant cells' growth is favored by fermentative glycosis by so-called "Warburg effect", but there are clear evidence that oxidative phosphorylation could be used, to some extent by some tumors to derived their energy [68,69]. During cancerogensis energetic metabolism is differently regulated, total AK activity being almost three times higher in nullipotent embryonal carcinoma cells compared to normal pluripotent human embryonic stem cells [70]. More, there are evidence of production of ATP by mitochondrial oxidative phosphorylation in neuroblastoma cells, two enzymes being involved in this process-AK2 and hexokinase-2 [71].…”