Ovarian cancer G protein-coupled receptor 1 inhibits A549 cells migration through casein kinase 2α intronless gene and neutral endopeptidase

Abstract

Background We have previously reported that a new intronless gene for casein kinase 2α (CK2α), CSNK2A3, is expressed in human cells. The promoter of the well-known CK2α, CSNK2A1, displays characteristics of a housekeeping gene, whereas CSNK2A3 has a characteristic of a regulated promoter with two TATA boxes and a CAAT box. GPR68, a family of the G protein-coupled receptors, is also known as ovarian cancer G protein-coupled receptor 1 (OGR1). In the current study, we analyzed the roles of CK2α genes and neutral endopeptidase (NEP), a key enzyme that influences a variety of malignancies, in the OGR1-induced inhibition of A549 cell migration. Methods We analyzed the transcript expressions of both the CK2α genes (CSNK2A1 and CSNK2A3) and NEP upon OGR1 overexpression. Protein expression of CK2α and NEP were also analyzed. We further elucidated the functional roles of both CK2α and NEP in the OGR1-induced inhibition of A549 cell migration in vitro using a wound-healing assay. We also analyzed the molecular mechanisms involved in the OGR1-induced inhibition of lung cancer cell migration. Results The findings of this study showed that OGR1 upregulated the expression of CSNK2A3 but not CSNK2A1 in the A549 cells. The findings further suggested OGR1 also upregulates the expression of NEP. The OGR1-induced inhibition of A549 cell migration was abrogated completely by inhibition of CK2α activity, whereas partial abrogation (~ 30%) was observed in the presence of NEP inhibition. The results also revealed that OGR1 regulates CSNK2A3 via activation of Rac1/cdc42 and MAPKs pathways. CK2 is ubiquitously expressed, and in contrast, is believed to be a constitutively active enzyme, and its regulation appears to be independent of known second messengers. Conclusion In the current study, we report for the first time the OGR1-induced regulation of CSNK2A3, CK2αP, and NEP in A549 cancer cells. Our study also decoded the downstream cellular proteins of OGR1 as well as the molecular mechanism involved in OGR1-induced inhibition of A549 cell migration. The findings of this research suggest the potential therapeutic targets to inhibit lung cancer progression.

Fusogenic peptide delivery of bioactive siRNAs targeting CSNK2A1 for treatment of ovarian cancer

“…While we did not observe any significant loss of cell viability after a 48-h treatment with DIV3W-siCSNK2A1 complexes, other studies have also demonstrated that knocking down CSNK2A1 does not result in a loss in cell viability without including supplemental drug treatments due to the many roles of CSNK2A1 in cell communication pathways in different cell types. 27 , 30 , 51 , 52 Silencing CSNK2A1 did reduce cell migration, which is consistent with previous reports that show upregulated CSNK2A1 expression contributes to increased cancer aggressiveness and decreased survivability rates in several cancer types. 48 , 51 , 53 Additionally, it has been demonstrated that CSNK2A1 expression mediates the PI3K-Akt-mTOR pathway, attributing to increased oncogenesis, migration, and invasion.…”

“… 27 , 30 , 51 , 52 Silencing CSNK2A1 did reduce cell migration, which is consistent with previous reports that show upregulated CSNK2A1 expression contributes to increased cancer aggressiveness and decreased survivability rates in several cancer types. 48 , 51 , 53 Additionally, it has been demonstrated that CSNK2A1 expression mediates the PI3K-Akt-mTOR pathway, attributing to increased oncogenesis, migration, and invasion. 49 Knockdown of CSNK2A1 via lentiviral transfection in gastric cancer cells inhibited migration across a scratch wound compared with cells with high CSNK2A1 expression.…”

Recent advances in acid sensing by G protein coupled receptors

“…[ 6 , 54 , 98 ]). As before, results do not seem to show any clear patterns: OGR1 was found to be involved in processes that promote or interfere with cancer progression [ 6 , 14 , 17 , 30 , 54 , 63 , 77 , 78 ]. Discrepancies may arise because some studies address a role for OGR1 in the host (tissue) whilst others look at OGR1 roles in cells making up the tumour tissue.…”

“…Research published in the past few years adds to the complicated picture. Several studies have investigated OGR1 in cancer, specifically in pancreatic, breast, ovarian, skin, liver, head and neck, colorectal and oesophageal cancer [ 5 , 6 , 14 , 18 , 30 , 33 , 48 , 54 , 63 , 77 , 78 , 88 , 96 , 98 , 101 ], ranging from pure expression (e.g. [ 5 , 48 ]) to functional studies in cells (e.g.…”

“…[ 5 , 48 ]) to functional studies in cells (e.g. [ 77 , 96 , 98 ]) and/or mice (e.g. [ 6 , 54 , 98 ]).…”