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Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition
- Source :
- Biochemical and biophysical research communications. 444(4)
- Publication Year :
- 2014
-
Abstract
- The PI3K/Akt/mTOR axis in lung cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for lung cancer. However, non-small cell lung cancer cells are resistant to BEZ235, a dual inhibitor of PI3K and mTOR. Interestingly, blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA dramatically sensitized the BEZ235-induced cell death, as evident from increased PARP cleavage. Furthermore, inhibition of Stat3 led to enhancement of cell death induced by LY294002, a PI3K inhibitor. Treatment of cells with a combination of BEZ235 and S3I-201 significantly induced the proapoptotic transcription factor, CHOP, and its targets, Bim and DR4. Knockdown of CHOP or Bim suppressed cell death stimulated by the combination treatment, implicating the involvement of these BEZ235/S3I-201-induced factors in pronounced cell death. Moreover, the BEZ235/S3I-201 combination enhanced TRAIL-induced cell death. Our results collectively suggest that blockage of Stat3 presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition.
- Subjects :
- STAT3 Transcription Factor
Programmed cell death
Lung Neoplasms
Biophysics
Antineoplastic Agents
CHOP
medicine.disease_cause
Biochemistry
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
medicine
Humans
LY294002
RNA, Small Interfering
STAT3
Molecular Biology
Protein kinase B
Lung
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
biology
Chemistry
TOR Serine-Threonine Kinases
RPTOR
Benzenesulfonates
Imidazoles
Cell Biology
Cell biology
Aminosalicylic Acids
Drug Resistance, Neoplasm
biology.protein
Cancer research
Quinolines
RNA Interference
Carcinogenesis
Signal Transduction
Subjects
Details
- ISSN :
- 10902104
- Volume :
- 444
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Biochemical and biophysical research communications
- Accession number :
- edsair.doi.dedup.....1bcc0223dee8144374aac2eedd8bbf18