Abstract
Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.
Highlights
Calpains are ubiquitous cysteine proteases activated by calcium signaling and/or epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) [1,2,3]
Our results have indicated that the specific inhibition of calpains activity by calpastatin accelerates metastatic dissemination to regional lymph nodes
Our results were obtained by analyzing the progression of melanoma in wild type (WT) and Calpastatin transgenic (CalpTG) mice injected subcutaneously with the highly metastatic B16-F10 cell line which shares the same C57BL/6 genetic background with tumor bearing mice
Summary
Calpains are ubiquitous cysteine proteases activated by calcium signaling and/or epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) [1,2,3]. Other calpain isoform expression is limited and tissue-specific. Both m- and m-calpain play essential roles in cellular homeostasis. They promote cell motility by modulating cytoskeleton organization through limited proteolysis, increase inflammation by facilitating NF-kB activation and leukocyte diapedesis, or promote angiogenesis through various mechanisms [4,5,6,7,8,9]. A dramatic activation of calpain results in cell death by apoptosis and necrosis [10,11]. Calpain intracellular activity is limited by their specific and ubiquitous inhibitor calpastatin [1]. Targeted disruption of Capn gene encoding m-calpain does not result in any phenotype in mice, with the exception of platelet dysfunction, whereas targeted disruption of Capns gene encoding
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
