title: Artesunate acts as fuel to fire in sensitizing HepG2 cells towards TRAIL mediated apoptosis via STAT3 inhibition and DR4 augmentation.
abstract: In the present study, we investigated in vitro, the role of artesunate (ATS) with comparable potency to oxaliplatin (OXP) in sensitizing tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) resistant HepG2 cells towards apoptosis. ATS in consistency with OXP was found to reverse TRAIL resistant HepG2 cells towards TRAIL mediated apoptosis by enhancing caspase-3 and cleavage of PARP. Additionally, ATS also suppressed the nuclear translocation of activated signal transducers and activators of transcription 3 (STAT3) thereby sensitizing the HepG2 cells towards only death receptor 4 (DR4) mediated apoptosis. Furthermore, ATS exposure in TRAIL resistant cells resulted in significant increase of both DR4/DR5 expression and STAT3 inhibition thereby arbitrating TRAIL mediated apoptosis in HepG2 cells. The increase in expression was comparable to that of STAT3 silenced cells. From all the above observations, we conclude that ATS up-regulated DR4 expression by targeting STAT3, which in turn sensitized HepG2 cells to TRAIL mediated apoptosis.
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur 613401, India.
authors.forename: M
authors.initials: M
authors.lastname: Ilamathi
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur 613401, India. Electronic address: sivaramakrishnan@scbt.sastra.edu.
authors.forename: V
authors.initials: V
authors.lastname: Sivaramakrishnan
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection
chemical_list: D037621:Artemisinins; D009944:Organoplatinum Compounds; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D050796:STAT3 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077150:Oxaliplatin; D000077332:Artesunate; D053148:Caspase 3
keywords: Apoptosis; Artesunate; Death receptor 4; Oxaliplatin; Signal transducers and activators of transcription 3; Tumour necrosis factor-related apoptosis-inducing ligand