Extracellular sialyltransferase st6gal1 in breast tumor cell growth and invasiveness.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
16
12
2021
accepted:
20
05
2022
revised:
09
05
2022
pubmed:
9
6
2022
medline:
18
11
2022
entrez:
8
6
2022
Statut:
ppublish
Résumé
The sialyltransferase ST6GAL1 that adds α2-6 linked sialic acids to N-glycans of cell surface and secreted glycoproteins is prominently associated with many human cancers. Tumor-native ST6GAL1 promotes tumor cell behaviors such as invasion and resistance to cell stress and chemo- and radio-treatments. Canonically, ST6GAL1 resides in the intracellular secretory apparatus and glycosylates nascent glycoproteins in biosynthetic transit. However, ST6GAL1 is also released into the extracellular milieu and extracellularly remodels cell surface and secreted glycans. The impact of this non-canonical extrinsic mechanism of ST6GAL1 on tumor cell pathobiology is not known. We hypothesize that ST6GAL1 action is the combined effect of natively expressed sialyltransferase acting cell-autonomously within the ER-Golgi complex and sialyltransferase from extracellular origins acting extrinsically to remodel cell-surface glycans. We found that shRNA knockdown of intrinsic ST6GAL1 expression resulted in decreased ST6GAL1 cargo in the exosome-like vesicles as well as decreased breast tumor cell growth and invasive behavior in 3D in vitro cultures. Extracellular ST6GAL1, present in cancer exosomes or the freely soluble recombinant sialyltransferase, compensates for insufficient intrinsic ST6GAL1 by boosting cancer cell proliferation and increasing invasiveness. Moreover, we present evidence supporting the existence novel but yet uncharacterized cofactors in the exosome-like particles that potently amplify extrinsic ST6GAL1 action, highlighting a previously unknown mechanism linking this enzyme and cancer pathobiology. Our data indicate that extracellular ST6GAL1 from remote sources can compensate for cellular ST6GAL1-mediated aggressive tumor cell proliferation and invasive behavior and has great clinical potential for extracellular ST6GAL1 as these molecules are in the extracellular space should be easily accessible targets.
Identifiants
pubmed: 35676533
doi: 10.1038/s41417-022-00485-y
pii: 10.1038/s41417-022-00485-y
pmc: PMC9663294
mid: NIHMS1841107
doi:
Substances chimiques
Sialyltransferases
EC 2.4.99.-
Glycoproteins
0
Polysaccharides
0
ST6GAL1 protein, human
EC 2.4.99.1
Antigens, CD
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1662-1675Subventions
Organisme : NCI NIH HHS
ID : R01 CA207504
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA235305
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM130915
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103390
Pays : United States
Organisme : NIGMS NIH HHS
ID : R43 GM134794
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL151333
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI140736
Pays : United States
Informations de copyright
© 2022. The Author(s).
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