Procathepsin L secretion, which triggers tumor progression, is regulated by Rab4A in human melanoma cells

Alice Barbarin (1) , Raymond Frade (1)

1 Immunochimie des Regulations Cellulaires et des Interactions Virales

The switch of human melanoma cell phenotype from non to highly tumorigenic and metastatic is triggered by the increase of procathepsin L secretion which modifies tumor microenvironment. Our aim was to identify components involved in the regulation of procathepsin L secretion in melanoma cells. We focused on Rab family members, i.e. Rab3A, Rab4A, Rab4B, Rab5A, Rab8A, Rab11A, Rab27A and Rab33A, involved in distinct regulatory pathways. From analysis of mRNA and protein expression of these Rab components and their knock down by specific siRNAs emerged that Rab4A protein is involved in the regulation of procathepsin L secretion. This result was strengthened as procathepsin L secretion was either inhibited by expression of Rab4A dominant negative mutant or increased by overexpression of the Rab4A wild type. Rab4A regulation: 1) discriminates between procathepsin L secretion and expression of intracellular cathepsin L forms; 2) did not modify other Rab proteins and GAPDH expression or IL-8 and MMP2 secretion; 3) still efficient on unglycosylated procathepsin L secretion. Thus, down- or up-regulation of Rab4A expression or Rab4A function triggered inhibition or increase of procathepsin L secretion, respectively. Furthermore, Rab4A regulation, by modifying procathepsin L secretion, switches the tumorigenic phenotype of human melanoma cells in nude mice.

Mots clés: Life Sciences

Alice Barbarin, Raymond Frade. Procathepsin L secretion, which triggers tumor progression, is regulated by Rab4A in human melanoma cells. Biochemical Journal, 2011, 437 (1), pp.97-107. ⟨10.1042/BJ20110361⟩. ⟨hal-00600761⟩