title: alpha-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells.
abstract: RRR-alpha-tocopherol ether linked acetic acid analog (alpha-TEA), is a potential chemotherapeutic agent for ovarian cancer. Pro-death and pro-life signaling pathways were studied to understand the anti-cancer actions of alpha-TEA on cisplatin-sensitive (A2780S) and -resistant (A2780/cp70R) human ovarian cancer cells. Both cell lines were refractory to Fas; whereas, alpha-TEA sensitized them to Fas signaling. alpha-TEA increased levels of Fas message, protein and membrane-associated Fas. Neutralizing antibodies to Fas or Fas L partially blocked alpha-TEA-induced apoptosis. alpha-TEA induced prolonged activation of c-Jun N-terminal kinase (JNK) and its substrate c-Jun; Bax conformational change; and cleavage of Bid and caspases-8, -9 and -3. Chemical inhibitors of JNK, and caspases blocked alpha-TEA-induced apoptosis. alpha-TEA decreased phosphorylation of protein kinase B (Akt/PKB) and extracellular signal-regulated kinase (ERK1/2), as well as cellular FLICE-like inhibitory protein (c-FLIP) and Survivin protein levels. Knockdown of Akt and ERK activity using phosphoinositide- 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MKK1) inhibitors enhanced alpha-TEA-induced apoptosis. Over-expression of constitutively active Akt2 and MKK1 blocked alpha-TEA-induced apoptosis. Collectively, data show alpha-TEA to be a potent apoptotic inducer of both cisplatin-sensitive and -resistant human ovarian cancer cells via activating death receptor Fas signaling and suppressing anti-apoptotic AKT and ERK targets.
authors.affiliation: School of Biological Sciences/C0900, University of Texas at Austin, 78712, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yu
authors.forename: Ming-chieh
authors.initials: MC
authors.lastname: Shun
authors.forename: Kristen
authors.initials: K
authors.lastname: Anderson
authors.forename: Hansong
authors.initials: H
authors.lastname: Chen
authors.forename: Bob G
authors.initials: BG
authors.lastname: Sanders
authors.forename: Kimberly
authors.initials: K
authors.lastname: Kline
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D024505:Tocopherols; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C491901:FAS protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun; D000077022:Survivin; D019014:fas Receptor; D014810:Vitamin E; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; C488288:2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid; D002945:Cisplatin; D024505:Tocopherols