Abl and Arg mediate cysteine cathepsin secretion to facilitate melanoma invasion and metastasis

Abstract

The incidence of melanoma is increasing, particularly in young women, and the disease remains incurable for many because of its aggressive, metastatic nature and its high rate of resistance to conventional, targeted, and immunological agents. Cathepsins are proteases that are critical for melanoma progression and therapeutic resistance. Intracellular cathepsins cleave or degrade proteins that restrict cancer progression, whereas extracellular cathepsins directly cleave the extracellular matrix and activate proinvasive proteases in the tumor microenvironment. Cathepsin secretion is markedly increased in cancer cells. We investigated the signaling pathways leading to increased cathepsin secretion in melanoma cells. We found that the nonreceptor tyrosine kinases Abl and Arg (Abl/Arg) promoted the secretion of cathepsin B and cathepsin L by activating transcription factors (namely, Ets1, Sp1, and NF-κB/p65) that have key roles in the epithelial-mesenchymal transition (EMT), invasion, and therapeutic resistance. In some melanoma cell lines, Abl/Arg promoted the Ets1/p65-induced secretion of cathepsin B and cathepsin L in a kinase-independent manner, whereas in other melanoma lines, Abl/Arg promoted the kinase-dependent, Sp1/Ets1/p65-mediated induction of cathepsin L secretion and the Sp1/p65-mediated induction of cathepsin B secretion. As an indication of clinical relevance, the abundance of mRNAs encoding Abl/Arg, Sp1, Ets1, and cathepsins was positively correlated in primary melanomas, and Abl/Arg-driven invasion in culture and metastasis in vivo required cathepsin secretion. These data suggest that drugs targeting Abl kinases, many of which are FDA-approved, might inhibit cathepsin secretion in some melanomas and potentially other aggressive cancers harboring activated Abl kinases.

Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

“…However, increased expression may constitute an important step in activation. Indeed, ABL1 and ABL2 mRNA/protein levels are increased in a majority of melanoma lines (25 were queried), which suggests that increased expression is likely critical for the disease process [40]. However, the kinases are only activated in 40–60% of the lines indicating that other alterations (e.g.…”

“…differences in the genetic make-up of the lines) also contribute to activation [40]. Importantly, ABL1 and/or ABL2 mRNAs are associated with disease progression in melanoma, breast cancer, and hepatocellular carcinoma [41, 40, 42, 43], confirming that mRNA upregulation is indeed an important step in ABL kinase activation. Consistent with these data, downregulation of microRNAs (miRNAs; miRs) that inhibit ABL1/2 expression, also drives disease development.…”

“…via MMP activaton) degrading the ECM [96]. Importantly, ABL kinases dramatically induce cathepsin expression and secretion by increasing mRNA expression, nuclear translocation and DNA binding activity of key transcription factors (SP1, ETS1, RELA) [40]. …”

“…ABL1 and ABL2 promote lung colonization of melanoma cells via MMP, NME1, and cathepsin-mediated pathways [69, 42, 40]. ABL2 promotes intravasation and spontaneous lung metastasis of MDA-MB-231 breast cancer cells [64].…”

“…In breast cancer cells, ABL1/ABL2 induce TAZ and STAT5A mRNAs, whereas in melanoma cells, they induce SP1 and ETS1 mRNAs; however, the mechanisms of upregulation have not yet been established [43, 40]. In some melanoma cells, ABL kinases increase RELA mRNA expression via a kinase-independent pathway [6, 120], whereas in other lines ABL1/ABL2 do not alter RELA expression, and instead induce its nuclear translocation via a kinase-dependent mechanism [40]. Importantly, the authors also provide the first evidence that ABL1 and ABL2 dramatically increase the DNA binding activities of SP1, ETS1 , and RELA to cathepsin promoters in melanoma cells [40].…”