Abstract
RAB7 is a small guanosine triphosphatase (GTPase) extensively studied as regulator of vesicular trafficking. Indeed, its role is fundamental in several steps of the late endocytic pathway, including endosome maturation, transport from early endosomes to late endosomes and lysosomes, clustering and fusion of late endosomes and lysosomes in the perinuclear region and lysosomal biogenesis. Besides endocytosis, RAB7 is important for a number of other cellular processes among which, autophagy, apoptosis, signaling, and cell migration. Given the importance of RAB7 in these cellular processes, the interest to study the role of RAB7 in cancer progression is widely grown. Here, we describe the current understanding of oncogenic and oncosuppressor functions of RAB7 analyzing cellular context and other environmental factors in which it elicits pro and/or antitumorigenic effects. We also discuss the role of RAB7 in cisplatin resistance associated with its ability to regulate the late endosomal pathway, lysosomal biogenesis and extracellular vesicle secretion. Finally, we examined the potential cancer therapeutic strategies targeting the different molecular events in which RAB7 is involved.
Highlights
IntroductionThe RAB (Ras-related in brain) protein family comprises small guanosine triphosphatases (GTPases) that are important regulators of membrane identity and of vesicular trafficking events [1,2,3,4]
The RAB (Ras-related in brain) protein family comprises small guanosine triphosphatases (GTPases) that are important regulators of membrane identity and of vesicular trafficking events [1,2,3,4].RAB7A is a small GTPase of the RAB family, ubiquitously expressed, mainly localized to late endosomes and with a pivotal role in endocytic trafficking
The reported RAB7 role as a tumor suppressor is based on the fact that it is a negative regulator of prostate cancer growth and invasion because it inhibits ligand-induced c-Met signaling, known to induce epithelial–mesenchymal transition (EMT), and it controls the perinuclear localization of lysosomes [98]
Summary
The RAB (Ras-related in brain) protein family comprises small guanosine triphosphatases (GTPases) that are important regulators of membrane identity and of vesicular trafficking events [1,2,3,4]. RAB7A regulates maturation of early endosome into late endosome, transport from early endosomes to late endosome and lysosomes, clustering and fusion of late endosomes and lysosomes in perinuclear region and lysosomal biogenesis [5,6] In addition of these functions, and related to them, RAB7A has many other cellular roles, being involved in autophagy [7,8], in apoptosis [9], in phagocytosis [10], in retromer regulation, mitophagy, and lipophagy as well as in cytoskeleton organization [5]. GTPase: a dominant negative mutant (RAB7T22N ) characterized by impaired nucleotide exchange, locking the protein in its inactive GDP-bound form, and a constitutively active mutant (RAB7Q67L ). The aim of this review is to describe the role of RAB7A in cancer progression and in chemoresistance and to illustrate the emerging and preliminary attempts to target RAB7A and late endocytic pathway as a novel strategy to cancer treatment
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