title: The calpain/calpastatin system has opposing roles in growth and metastatic dissemination of melanoma.
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.
authors.affiliation: Unité Mixte de Recherche 702 (UMR S 702), Université Pierre-et-Marie-Curie Paris VI et Institut National de la Santé et de la Recherche Médicale, Hôpital Tenon, Paris, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Raimbourg
authors.forename: Joëlle
authors.initials: J
authors.lastname: Perez
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.forename: Aurélie
authors.initials: A
authors.lastname: Prignon
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hanouna
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D002135:Calcium-Binding Proteins; C033668:calpastatin; D002154:Calpain
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