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.

• Authors: Rakshamani Tripathi, Leann S Fiore, Dana L Richards, Yuchen Yang, Jinpeng Liu, Chi Wang, Rina Plattner
• Journal: Science signaling (Sci Signal) Vol. 11 Issue 518 (02 20 2018) ISSN: 1937-9145 [Electronic] United States
• PMID: 29463776 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Antineoplastic Agents
• Oncogene Proteins v-abl
• Pyrimidines
• ARG tyrosine kinase
• Protein-Tyrosine Kinases
• Cathepsins
• Cysteine Proteases
• nilotinib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cathepsins (genetics, metabolism)
• Cell Line, Tumor
• Cysteine Proteases (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (drug therapy, enzymology, genetics, metabolism)
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Oncogene Proteins v-abl (genetics, metabolism)
• Protein-Tyrosine Kinases (genetics, metabolism)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects, genetics)
• Xenograft Model Antitumor Assays (methods)