Leucine-rich repeat containing 4 act as an autophagy inhibitor that restores sensitivity of glioblastoma to temozolomide.
Oncogene
; 39(23): 4551-4566, 2020 06.
Article
in En
| MEDLINE
| ID: mdl-32372061
ABSTRACT
Temozolomide (TMZ) insensitivity and resistance are major causes of treatment failure and poor prognosis for GBM patients. Here, we identify LRRC4 as a novel autophagy inhibitor that restores the sensitivity of GBMs to TMZ. LRRC4 was associated with the DEPTOR/mTOR complex, and this interaction resulted in autophagy inhibition. Further investigation demonstrated that the PDZ binding domain of LRRC4 binds to the PDZ domain of DEPTOR. This binding decreases the half-life of DEPTOR via ubiquitination, thus inhibiting GBM cell autophagy and increasing the TMZ treatment response of GBM. Combined LRRC4 expression and TMZ treatment prolonged the survival of mice with tumour xenografts. Furthermore, the levels of LRRC4, DEPTOR and autophagy are clinically relevant for GBM, indicating that LRRC4 is likely to have significant potential as a therapeutic marker and target for TMZ treatment in glioma patients.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autophagy
/
Brain Neoplasms
/
Glioblastoma
/
Antineoplastic Agents, Alkylating
/
Temozolomide
/
Nerve Tissue Proteins
Type of study:
Diagnostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Oncogene
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2020
Document type:
Article
Affiliation country:
China