ReferenceID 3476
Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs
Free Radic Biol Med
STAT3 is a transcription factor constitutively activated in a variety of cancers that has a critical role in the inhibition of apoptosis and induction of chemoresistance. Inhibition of the STAT3 signaling pathway suppre
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Record Fields
Scalar fields from the final reference record.
- Reference Id
- 3476
- Evidence Id
- 20066
- Core Evidence Id
- 20066
- Source Reference Id
- 255
- Herb2 Reference Id
- HBREF000492
- Subject Paper Key
- HBIN022473_24095958
- Pubmed Id
- 24095958
- Doi
- 10.1016/j.freeradbiomed.2013.09.015
- Paper Title
- Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs
- Paper Abstract
- STAT3 is a transcription factor constitutively activated in a variety of cancers that has a critical role in the inhibition of apoptosis and induction of chemoresistance. Inhibition of the STAT3 signaling pathway suppresses cell survival signals and leads to apoptosis in cancer cells, suggesting that direct inhibition of STAT3 function is a viable therapeutic approach. Herein, we identify the naturally occurring sesquiterpene lactone cynaropicrin as a potent inhibitor of both IL-6-inducible and constitutive STAT3 activation (IC50=12 μM). Cynaropicrin, which contains an α-β-unsaturated carbonyl moiety and acts as potent Michael reaction acceptor, induces a rapid drop in intracellular glutathione (GSH) concentration, thereby triggering S-glutathionylation of STAT3. Furthermore, glutathione ethylene ester, the cell permeable form of GSH, reverts the inhibitory action of cynaropicrin on STAT3 tyrosine phosphorylation. These findings suggest that this sesquiterpene lactone is able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein to regulate its function. STAT3 inhibition led to the suppression of two anti-apoptotic genes, Bcl-2 and survivin, in DU145 cells that constitutively express active STAT3. This event may be responsible for the decline in cell viability after cynaropicrin treatment. As revealed by PI/annexin-V staining, PARP cleavage, and DNA ladder formation, cynaropicrin cytotoxicity is mediated by apoptosis. Finally, cynaropicrin displayed a slight to strong synergism with two well-established chemotherapeutic drugs, cisplatin and docetaxel. Taken together our studies suggest that cynaropicrin suppresses the STAT3 pathway, leading to the down-regulation of STAT3-dependent gene expression and chemosensitization of tumour cells to chemotherapy.
- Journal
- Free Radic Biol Med
- Publish Year
- 2013
- Experiment Subject
- du145 cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs
- Bilingual Status
- semi_complete