Abl Kinase Regulation of Cysteine Cathepsin Secretion During Melanoma Invasion and Metastasis

Unlike most other cancers, the incidence of melanoma is continuing to increase, particularly in young women, and the disease remains incurable for many due to its aggressive, metastatic nature, and high rate of resistance to conventional, targeted, and immunological agents. Cathepsin proteases are critical for melanoma progression and therapeutic resistance. Intracellular cathepsins cleave/degrade proteins that restrict cancer progression, while extracellular cathepsins directly cleave extracellular matrix and activate pro-invasive proteases in the tumor microenvironment. Cathepsin secretion is dramatically increased in cancer cells; however, the signaling pathways have not been extensively studied. Here, we describe new pathways leading to cathepsin secretion in melanoma cells. We show that Abl and Arg non-receptor tyrosine kinases (Abl/Arg) promote cathepsin B/L secretion by activating transcription factors with key roles in epithelial-mesenchymal transition (EMT), invasion, and therapeutic resistance (Ets1, Sp1, NF-κB/p65). In some melanoma cells, Abl/Arg drive an Ets1/p65->cathepsin pathway via a kinase independent mechanism, whereas, in others, Abl/Arg promote kinase-dependent Sp1/Ets1/p65->cathepsin L and Sp1/p65->cathepsin B pathways. The signaling pathways we identify are functionally and clinically relevant, as Abl/Arg, Sp1, Ets1, and cathepsin mRNAs are correlated in primary melanomas, and Abl/Argdriven invasion and metastasis requires cathepsin secretion. These data are significant as they indicate that drugs targeting Abl kinases, many of which are FDA-approved, might serve as cathepsin secretion inhibitors for melanomas expressing activated Abl kinases. The data also have important translational relevance given the renewed interest in targeting extracellular cathepsins as a therapeutic strategy for aggressive cancers. Abl and Arg induce cathepsin protein and secretion in melanoma via p65-dependent Ets1/Sp1 pathways, and drive invasion/metastasis in a cathepsin-dependent manner.