title: Deoxyelephantopin impairs growth of cervical carcinoma SiHa cells and induces apoptosis by targeting multiple molecular signaling pathways.
abstract: Deoxyelephantopin, a sesquiterpene lactone extracted and purified from Elephantopus scaber, has been shown to exhibit antitumor and hepatoprotective activities. The purpose of this study was to investigate the antiproliferative and apoptosis-inducing properties of deoxyelephantopin in SiHa cells and to elucidate the underlying molecular mechanisms. Deoxyelephantopin inhibited growth of SiHa cells and triggered apoptosis. Apoptosis was accompanied by sequential activation of caspases (8, 9, 3, and 7) and reactive oxygen species (ROS) production. Downregulation of antiapoptotic proteins (Bcl2 and Bcl-xL) and upregulation of apoptotic protein (bax) were also detected. Our results demonstrated that deoxyelephantopin-induced G2/M phase arrest was associated with a marked increase in the levels of p53 and p21 and a decrease in phospho-signal transducer and activator of transcription 3 (pSTAT3-Tyr705), cyclin-dependent kinase 1 (cdc2), and cyclin B1. The expression of p-Akt and p-mTOR was downregulated. p-ERK was inhibited while p-JNK and p-p38 was activated on deoxyelephantopin treatment. Our findings provided the first evidence that STAT3/p53/p21 signaling, MAPK pathway, PI3k/Akt/mTOR pathway, caspase cascades, and ROS play critical roles in deoxyelephantopin-induced G2/M phase arrest and apoptosis of SiHa cells.
authors.affiliation: Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India, farha.ak@gmail.com.
authors.forename: Arakkaveettil Kabeer
authors.initials: AK
authors.lastname: Farha
authors.forename: Sethumadhavannair Rajalekshmi
authors.initials: SR
authors.lastname: Dhanya
authors.forename: Sivasankaran Nair
authors.initials: SN
authors.lastname: Mangalam
authors.forename: Balakrishnan Sreedevi
authors.initials: BS
authors.lastname: Geetha
authors.forename: Panickamparambil Gopalakrishnan
authors.initials: PG
authors.lastname: Latha
authors.forename: Prathapan
authors.initials: P
authors.lastname: Remani
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019659:Asteraceae / Q000737:chemistry; D016203:CDC2 Protein Kinase; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002584:Cervix Uteri / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056744:Cyclin B1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; C534699:CCNB1 protein, human; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007783:Lactones; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C528427:deoxyelephantopin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases