The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular
Mechanisms Differently Affected by Rab5a in the Early and Late Stages
#MMPMID27023526
Maroni P
; Bendinelli P
; Resnati M
; Matteucci E
; Milan E
; Desiderio MA
Int J Mol Sci
2016[Mar]; 17
(4
): 443
PMID27023526
show ga
Autophagy favours metastatic growth through fuelling energy and nutrients and
resistance to anoikis, typical of disseminated-tumour cells. The autophagic
process, mediated by a unique organelle, the autophagosome, which fuses with
lysosomes, is divided into three steps. Several stages, especially early
omegasome formation and isolation-membrane initiation, remain controversial;
molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle
traffic for autophagosome formation. We examined Rab5a involvement in the
function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated,
interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was
performed in human specimens of bone metastasis and pair-matched breast
carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated
in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231
cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with
Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were
exposed to two inhibitors of autolysosome function, and LC3II and p62 expression
was measured. We showed basal autophagy in bone-metastatic cells and the pivotal
role of Rab5a together with Beclin 1 between the early stages, elongation of
isolation membrane/closed autophagosome mediated by Atg7, and the
late-degradative stages. This regulatory network might occur in bone-metastasis
and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and
conferring phenotypic characteristics for dissemination.
|Autophagy
[MESH]
|Autophagy-Related Protein 7/antagonists & inhibitors/genetics/metabolism
[MESH]
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