title: ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer.
abstract: Evidences suggest that tumor microenvironment may play an important role in cancer drug resistance. Sphingosine kinase 2 (SphK2) is proposed to be the key regulator of sphingolipid signaling. This study is aimed to investigate whether the combination of molecular targeting therapy using a specific inhibitor of SphK2 (ABC294640), with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells. Our results revealed that NSCLC cells' sensitivity to TRAIL is correlated with the level of SphK2. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect. Combination therapy with ABC294640 increased the activity of caspase-3/8 and up-regulated the expression of death receptors (DR). Additional investigations revealed that translocation of DR4/5 to the cell membrane surface was promoted by adding ABC294640. However, expression of anti-apoptosis proteins such as Bcl(-)2 and IAPs was not significantly modified by this SphK2 inhibitor. Overall, this work demonstrates that SphK2 may contribute to the apoptosis resistance in NSCLC, thus indicating a new therapeutic target for resistant NSCLC cells.
authors.affiliation: a Department of Radiation and Medical Oncology ; Zhongnan Hospital of Wuhan University ; Wuhan , PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Chunxu
authors.initials: C
authors.lastname: Yang
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.forename: Zijie
authors.initials: Z
authors.lastname: Mei
authors.forename: Mingjun
authors.initials: M
authors.lastname: Shi
authors.forename: Shaoxing
authors.initials: S
authors.lastname: Sun
authors.forename: Liu
authors.initials: L
authors.lastname: Shi
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wang
authors.forename: Yacheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Li
authors.forename: Conghua
authors.initials: C
authors.lastname: Xie
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058990:Molecular Targeted Therapy / Q000379:methods; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011725:Pyridines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D000099157:Sphingosine Kinase; C105190:TNFRSF10A protein, human; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C000594250:sphingosine kinase 2, human
keywords: ABC294640, 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide; Bcl-2, B-cell lymphoma 2; Cer, ceramide; DISC, death-induced signaling complex; DR4, death receptor 4; DR5, death receptor 5; MTT, (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; NSCLC; NSCLC, non-small cell lung cancer; S1P, sphingosine-1-phosphate; SphK2, sphingosine kinase 2; TRAIL; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; death receptor; resistance; sphingosine kinase 2