The USP10/13 inhibitor, spautin-1, attenuates the progression of glioblastoma by independently regulating RAF-ERK mediated glycolysis and SKP2

Glioblastoma is a malignant brain tumor with poor prognosis. Though several dysregulated pathways were found to mediate the tumor progression, hyperactivation of RAS-RAF-ERK pathway, enhanced glycolysis and SKP2 are associated with several glioblastomas. Recent findings on the role of USP10 in the t...

Full description

Saved in:
Bibliographic Details
Published in:Biochimica et biophysica acta. Molecular basis of disease 2024-10, Vol.1870 (7), p.167291, Article 167291
Main Authors: Kona, Swathi V., Kalivendi, Shasi V.
Format: Article
Language:English
Subjects:
Deubiquitinases
Glioblastoma
Glycolysis
RAF-ERK
SKP2
Spautin-1
USP10
USP13
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Glioblastoma is a malignant brain tumor with poor prognosis. Though several dysregulated pathways were found to mediate the tumor progression, hyperactivation of RAS-RAF-ERK pathway, enhanced glycolysis and SKP2 are associated with several glioblastomas. Recent findings on the role of USP10 in the transition from pro-neural to mesenchymal subtype of glioblastoma and, USP13 in the stabilization of RAF1 in mouse embryonic stem cells prompted us to examine their role in the mechanisms mediating the progression of glioblastoma. In the present study, we have examined the role of spautin-1, a pharmacological inhibitor of USP10 and USP13 in the mechanisms mediating glioblastoma. Our results indicate that spautin-1 as well as knockdown of its downstream targets, USP10 and USP13, reduced the proliferation and migration of glioblastoma cells. Also, spautin-1 mediated inhibition of RAF-ERK pathway or inhibition of RAF1 and MEK1 per se reduced the glycolytic function via PKM2/Glut-1 and inhibited the progression of glioblastoma. Further, the protooncogene, SKP2, which was shown to be a direct target of USP10 /USP13 was also reduced by spautin-1. While inhibition of SKP2 enhanced its downstream target p21, no apparent changes in the RAF-ERK levels or glycolytic function were evident. Also, inhibition of MEK1 did not affect SKP2 levels, indicating that these two pathways act independent of each other. Overall, our findings indicate that spautin-1 by virtue of its inhibitory effects on USP10/13 counteracts RAS-RAF-ERK mediated glycolysis and SKP2 that are critical in the progression of glioblastoma. Hence, further preclinical validation is warranted for taking the present observations forward. [Display omitted] •Spautin-1 and knockdown of USP10/USP13 inhibits the progression of glioblastoma.•Inhibition of RAF-ERK axis by Spautin-1 affects glycolytic function via Glut-1 & PKM2.•Spautin-1/knockdown of USP13 downregulates SKP2 levels.•SKP2 and RAF-ERK axis play independent roles in Spautin-1 mediated effects.
ISSN:0925-4439
1879-260X
1879-260X
DOI:10.1016/j.bbadis.2024.167291