Dysregulation of adenosine kinase isoforms in breast cancer

Abstract

Dysregulated adenosine signaling pathway has been evidenced in the pathogenesis of breast cancer. However, the role of adenosine kinase (ADK) in tumorigenesis remains unclear while it crucially regulates the removal and availability of adenosine. ADK has two isoforms that localize to discrete subcellular spaces: i.e., nuclear, long-isoform (ADK-L) and cytosolic, short-isoform (ADK-S). We hypothesized that these two ADK isoforms would be differentially expressed in breast cancer and may contribute to divergent cellular actions in cancer. In this study, we examined the expression profiles of ADK isoforms in breast cancer tissues from 46 patient and followed up with an in vitro investigation by knocking down the expression of ADK-L or ADK-S using CRISPR gene editing to evaluate the role of ADK isoform in cancer progression and metastasis of cultured triple-negative breast cancer cell line MDA-MB-231. We demonstrated that (i) ADK-L expression level was significantly increased in breast cancer tissues versus paired normal tissues adjacent to tumor, whereas the ADK-S expression levels were not significantly different between cancerous and normal tissues; (ii) CRISPR/Cas9-mediated downregulation of ADK isoforms, led to suppressed cellular proliferation, division, and migration of cultured breast cancer cells; (iii) ADK-L knockdown significantly upregulated gene expression of matrix metalloproteinase (ADAM23, 9.93-fold; MMP9, 24.58-fold) and downregulated expression of cyclin D2 (CCND2,-30.76-fold), adhesive glycoprotein THBS1 (-8.28fold), and cystatin E/M (CST6,-16.32-fold). Our findings suggest a potential role of ADK-L in mitogenesis, tumorigenesis, and tumor-associated tissue remodeling and invasion; and the manipulation of ADK-L holds promise as a therapeutic strategy for aggressive breast cancer.

Oncogene-mediated metabolic gene signature predicts breast cancer outcome

“…Adenosine kinase (ADK) is also a key metabolic enzyme in the removal of adenosine that is tightly regulated in healthy cells. Adenosine signaling is associated with breast carcinoma and it is identified that downregulation of ADK decreases proliferation, migration, and invasion of TNBC cells, suggesting a functional role of ADK in TNBC 50 . Our study identified a new 5-gene metabolic signature (comprising of TALDO1, GPI, LDHA, SHMT2, and ADK) that is a more powerful prognostic marker than any of the single genes alone.…”

Drug-driven reclassification of multiple tumour subtypes reveals intrinsic molecular concordance of therapy across histologically disparate cancers

“…In our analysis, ADK-VCL, TNFRSF9 and LTB, as the top three most connected genes, were identified as novel cancer genes for further investigation. Adenosine kinase (ADK) has an important role in mitosis, tumorigenesis, tumor-associated tissue remodeling, and invasion, and manipulation of ADK has the potential to be a therapeutic strategy for invasive breast cancer [24]. Vinculin (VCL) is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, which interacts with many focal adhesion proteins and has been found to be closely linked to tumor migration [25].…”

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

“…The differences in the expression of two ADK isoforms are observed in the cases of breast cancer [62]. The changes in the tumor tissue primarily concerned ADK-L in comparison with healthy tissue.…”

“…In addition to nervous system disorders [50,52,57], the changes in the level of ADK enzyme attract researchers who study diabetes [58,59], vascular inflammation [60,61], and cancer [5,62].…”

“…The adenosine-ATP catalytic cascade is initiated via ADK-mediated phosphorylation of adenosine into AMP rather than its deamination to inosine [13] Breast cancer (n = 46 patients) and breast cancer MDA-MB-231 cell line Protein level ADK-L expression was significantly increased in breast cancer tissue; ADK downregulation suppressed proliferation, viability, migration, and invasion of cancer cells [62] Colorectal cancer (n = 10 patients) Gene expression ADK expression is higher in tumor than in healthy tissue [65] Colorectal cancer (n = 40 patients) Enzyme activity Higher in tumor than in healthy tissue (p < 0.01) [66] Glioma (n = 45 patients) Gene and protein expression levels…”