Abstract
BackgroundAcquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown.MethodsSmall interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay.ResultsWe demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase.ConclusionsOur findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.
Highlights
Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells
Our findings suggest that the interaction between Annexin A2 (Anxa2) and receptor for activated protein C kinase 1 (Rack1)/Src is responsible for the association between drug resistance and aggressive behavior in breast cancer cells
Rack1 is required for Anxa2 Tyr23 phosphorylation and enhanced invasiveness of drug-resistant breast cancer cells To determine whether Rack1 is necessary for Anxa2 tyrosine phosphorylation, we silenced the expression of Rack1 in two drug-resistant breast cancer cell lines using two different Rack1-specific siRNAs
Summary
Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. The accurate molecular mechanisms underlying the regulation of Anxa tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. One common mechanism is that cancer cells can evolve additional capabilities, such as enhanced invasion and metastasis with the acquisition of resistance. These abilities are often associated with reprogramming of intracellular gene expression and activation of the corresponding intracellular signaling pathways [2,3,4,5]. Determining the molecular mechanisms governing the aggressive behavior of drug-resistant tumors is critical for designing highly effective therapeutic strategies
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