Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Department of Pathology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Sci Signal. 2018 Feb 20;11(518):eaao0422. doi: 10.1126/scisignal.aao0422.
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.
黑色素瘤的发病率正在上升，尤其是在年轻女性中，由于其侵袭性、转移性和对传统、靶向和免疫治疗药物的高耐药性，许多患者的疾病仍然无法治愈。组织蛋白酶是对黑色素瘤进展和治疗耐药性至关重要的蛋白酶。细胞内组织蛋白酶可切割或降解限制癌症进展的蛋白质，而细胞外组织蛋白酶则直接切割细胞外基质，并激活肿瘤微环境中的促侵袭蛋白酶。癌细胞中组织蛋白酶的分泌显著增加。我们研究了导致黑色素瘤细胞中组织蛋白酶分泌增加的信号通路。我们发现，非受体酪氨酸激酶 Abl 和 Arg（Abl/Arg）通过激活转录因子（即 Ets1、Sp1 和 NF-κB/p65）促进组织蛋白酶 B 和组织蛋白酶 L 的分泌，这些转录因子在上皮-间充质转化（EMT）、侵袭和治疗耐药性中起关键作用。在一些黑色素瘤细胞系中，Abl/Arg 以激酶非依赖性方式促进 Ets1/p65 诱导的组织蛋白酶 B 和组织蛋白酶 L 的分泌，而在其他黑色素瘤系中，Abl/Arg 促进激酶依赖性、Sp1/Ets1/p65 介导的组织蛋白酶 L 分泌诱导和 Sp1/p65 介导的组织蛋白酶 B 分泌诱导。作为临床相关性的一个迹象，编码 Abl/Arg、Sp1、Ets1 和组织蛋白酶的 mRNA 的丰度在原发性黑色素瘤中呈正相关，并且 Abl/Arg 驱动的体外侵袭和体内转移需要组织蛋白酶分泌。这些数据表明，针对 Abl 激酶的药物（其中许多已获得 FDA 批准）可能会抑制某些黑色素瘤和其他含有激活的 Abl 激酶的侵袭性癌症中的组织蛋白酶分泌。
