Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/10361
Title
RAB7 counteracts PI3K-driven macropinocytosis activated at early stages of melanoma development.
Author(s)
Date issued
2015-05-20
Citation
Oncotarget . 2015;6(14):11848-62
Language
Inglés
Document type
journal article
Abstract
Derailed endolysosomal trafficking is emerging as a widespread feature of aggressive neoplasms. However, the oncogenic signals that alter membrane homeostasis and their specific contribution to cancer progression remain unclear. Understanding the upstream drivers and downstream regulators of aberrant vesicular trafficking is distinctly important in melanoma. This disease is notorious for its inter- and intra-tumoral heterogeneity. Nevertheless, melanomas uniformly overexpress a cluster of endolysosomal genes, being particularly addicted to the membrane traffic regulator RAB7. Still, the underlying mechanisms and temporal determinants of this dependency have yet to be defined. Here we addressed these questions by combining electron microscopy, real time imaging and mechanistic analyses of vesicular trafficking in normal and malignant human melanocytic cells. This strategy revealed Class I PI3K as the key trigger of a hyperactive influx of macropinosomes that melanoma cells counteract via RAB7-mediated lysosomal degradation. In addition, gain- and loss-of-function in vitro studies followed by histopathological validation in clinical biopsies and genetically-engineered mouse models, traced back the requirement of RAB7 to the suppression of premature cellular senescence traits elicited in melanocytes by PI3K-inducing oncogenes. Together, these results provide new insight into the regulators and modes of action of RAB7, broadening the impact of endosomal fitness on melanoma development.
Subject
ONCOGENE-INDUCED SENESCENCE | ENDOPLASMIC-RETICULUM | C-MYC | RAS | TRAFFICKING | MUTATIONS | AUTOPHAGY | BIOGENESIS | MECHANISMS | EXPRESSION
MESH
Animals | Cell Line, Tumor | Fluorescent Antibody Technique | Heterografts | Humans | Immunoblotting | Melanoma | Mice | Microscopy, Electron, Transmission | Phosphatidylinositol 3-Kinases | Pinocytosis | Transfection | rab GTP-Binding Proteins | ONCOGENE-INDUCED SENESCENCE
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