title: Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug             resistance.
abstract: Recent research has demonstrated that aberrant sphingolipid signaling is             an important mechanism of chemoresistance in solid tumors. Sphingosine kinase             (Sphk), the primary enzyme metabolizing the sphingolipid ceramide into sphingosine-1-phosphate             (S1P), is a primary mediator of breast cancer promotion, survival and chemoresistance.             However, to date the mechanism of Sphk-mediated drug resistance is poorly understood.             Using the dual sphingosine kinase isozyme inhibitor, SKI-II (4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol),             we explored the effects of sphingosine kinase inhibition on multi-drug-resistant             breast cancer cells. We demonstrate that SKI-II alters endogenous sphingolipid             signaling and decreases cancer proliferation, survival and viability. Furthermore,             pharmacological inhibition of Sphk1/2 induced intrinsic apoptosis in these cells             through modulation of the NF-κB pathway. SKI-II decreases NF-κB transcriptional             activity through altered phosphorylation of the p65 subunit. Taken together, these             results suggest that Sphk may be a promising therapeutic target in chemoresistant             cancers.
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine,                     New Orleans, LA 70112, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Antoon
authors.forename: Martin D
authors.initials: MD
authors.lastname: White
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Beckman
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D013844:Thiazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol