title: Isocryptotanshinone, a STAT3 inhibitor, induces apoptosis and pro-death autophagy in A549 lung cancer cells.
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.
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Guo
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Luo
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: b Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Pang
authors.affiliation: c Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang , China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: b Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China.
authors.forename: Ailin
authors.initials: A
authors.lastname: Liu
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Jinjian
authors.initials: J
authors.lastname: Lu
authors.affiliation: d Department of Chemistry , Hong Kong Baptist University , Kowloon Tong , Hong Kong.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Chen
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D045784:Abietanes; D000970:Antineoplastic Agents; D010616:Phenanthrenes; D011809:Quinones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000625872:isocryptotanshinone; C037886:cryptotanshinone
keywords: Apoptosis; STAT3; autophagy; isocryptotanshinone