GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

Background: Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown. Methods: Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein–coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitro cellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments. Results: Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating β-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-κB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of β-Arrestin 2, MAPKs and NF-κB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the β-Arrestin 2/MAPKs/NF-κB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells. Conclusion: Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.