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Isocryptotanshinone, a STAT3 inhibitor, induces apoptosis and pro-death autophagy in A549 lung cancer cells
- Source :
- Journal of drug targeting. 24(10)
- Publication Year :
- 2016
-
Abstract
- Signal transducer and activator of transcription 3 (STAT3) is a potential drug target for chemotherapy. Cryptotanshinone (CTS) was identified as a potent STAT3 inhibitor, while the effect of other tanshinones remains unknown. In this study, the influence of eight tanshinones on STAT3 activity was initially screened and isocryptotanshinone (ICTS) significantly inhibited STAT3 activity in a dual luciferase assay. ICTS inhibited the constitutive and inducible phosphorylation of STAT3 at Y705 without affecting the phosphorylation of STAT3 at S727 in A549 lung cancer cells. Furthermore, ICTS inhibited the nuclear translocation of STAT3. Compared with CTS, ICTS exhibited a stronger inhibitory effect on STAT3 phosphorylation and on A549 cytotoxicity. ICTS induced autophagy as evidenced by the accumulation of autophagic vacuoles and the increased expression of LC3 protein and autophagosomes. ICTS-induced cell death was partially reversed by the autophagy inhibitor chloroquine. The docking assay predicted that both ICTS and CTS bind the SH2 domain of STAT3. ICTS formed hydrogen bonds and pi-pi interaction with the nearby amino acid residues of Lys591, Arg609, and Ser636. These findings suggested that ICTS, a natural compound, is a potent STAT3 inhibitor. ICTS induced apoptosis and pro-death autophagy in A549 cells.
- Subjects :
- 0301 basic medicine
STAT3 Transcription Factor
Programmed cell death
Time Factors
Pharmaceutical Science
Antineoplastic Agents
Apoptosis
Pharmacology
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
parasitic diseases
Autophagy
Humans
Phosphorylation
STAT3
Cytotoxicity
Cell Proliferation
A549 cell
Binding Sites
biology
Dose-Response Relationship, Drug
Quinones
Phenanthrenes
Molecular Docking Simulation
030104 developmental biology
030220 oncology & carcinogenesis
Abietanes
Cancer research
biology.protein
STAT protein
Protein Binding
Subjects
Details
- ISSN :
- 10292330
- Volume :
- 24
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Journal of drug targeting
- Accession number :
- edsair.doi.dedup.....0195d7f2e17ce0158c5654a6fc53ee64