Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance.
Proc Natl Acad Sci U S A
; 112(30): 9406-11, 2015 Jul 28.
Article
in En
| MEDLINE
| ID: mdl-26170313
ABSTRACT
Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Carrier Proteins
/
Gene Expression Regulation, Neoplastic
/
Glioblastoma
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Drug Resistance, Neoplasm
/
Glucose
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2015
Type:
Article