Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia
Journal
Cancers
ISSN
2072-6694
Date Issued
2020
Author(s)
Carlos Sanhueza
Manuel Valenzuela-Valderrama
Pamela Contreras
Lorena Lobos-González
América Campos
Sergio Wehinger
Álvaro Lladser
Rolf Kiessling
Lisette Leyton
Andrew F.G. Quest
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:p>Caveolin-1 (CAV1) is a well-established nitric oxide synthase inhibitor, whose function as a tumor suppressor is favored by, but not entirely dependent on, the presence of E-cadherin. Tumors are frequently hypoxic and the activation of the hypoxia-inducible factor-1α (HIF1α) promotes tumor growth. HIF1α is regulated by several post-translational modifications, including S-nitrosylation. Here, we evaluate the mechanisms underlying tumor suppression by CAV1 in cancer cells lacking E-cadherin in hypoxia. Our main findings are that CAV1 reduced HIF activity and Vascular Endothelial Growth Factor expression in vitro and in vivo. This effect was neither due to reduced HIF1α protein stability or reduced nuclear translocation. Instead, HIF1α S-nitrosylation observed in hypoxia was diminished by the presence of CAV1, and nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) reduced HIF1α transcriptional activity in cells to the same extent as observed upon CAV1 expression. Additionally, arginase inhibition by (S)-(2-Boronoethyl)-L-cysteine (BEC) partially rescued cells from the CAV1-mediated suppression of HIF1α transcriptional activity. In vivo, CAV1-mediated tumor suppression was dependent on NOS activity. In summary, CAV1-dependent tumor suppression in the absence of E-cadherin is linked to reduced HIF1α transcriptional activity via diminished NOS-mediated HIF1α S-nitrosylation.</jats:p>
Cite this document
Sanhueza, C., Bennett, J. C., Valenzuela-Valderrama, M., Contreras, P., Lobos-González, L., Campos, A., Wehinger, S., Lladser, Á., Kiessling, R., Leyton, L., & Quest, A. F. G. (2020). Caveolin-1-mediated tumor suppression is linked to reduced hif1α s-nitrosylation and transcriptional activity in hypoxia. Cancers, 12(9), 2349. https://doi.org/10.3390/cancers12092349
Subjects
caveolin-1
;
hif1α
;
hypoxia
;
s-nitrosylation
;
tumor suppression
;
vegf
;
caveolin 1
;
glucose transporter 1
;
hypoxia inducible factor 1alpha
;
lactate dehydrogenase a
;
n(g) nitroarginine methyl ester
;
nitric oxide synthase
;
uvomorulin
;
vasculotropin
;
vasculotropin a
;
animal cell
;
animal experiment
;
animal model
;
antineoplastic activity
;
article
;
cell hypoxia
;
controlled study
;
enzyme activation
;
half life time
;
hek293t cell line
;
ht-29 cell line
;
human
;
human cell
;
immunofluorescence
;
in vitro study
;
in vivo study
;
mda-mb-231 cell line
;
mouse
;
nonhuman
;
polymerase chain reaction
;
protein analysis
;
protein degradation
;
protein expression
;
protein function
;
protein stability
;
protein structure
;
protein targeting
;
s-nitrosylation
;
transcription initiation