title: Inhibition of ceramide glucosylation sensitizes lung cancer cells to ABC294640, a first-in-class small molecule SphK2 inhibitor.
abstract: Sphingosine kinase 2 (SphK2) is proposed as a novel oncotarget for lung cancer. Here, we studied the anti-lung cancer cell activity by ABC294640, a first-in-class SphK2 inhibitor. We showed that ABC294640 suppressed growth of primary and A549 human lung cancer cells, but sparing SphK2-low lung epithelial cells. Inhibition of SphK2 by ABC294640 increased ceramide accumulation, but decreased pro-survival sphingosine-1-phosphate (S1P) content, leading to lung cancer cell apoptosis activation. Significantly, we show that glucosylceramide synthase (GCS) might be a major resistance factor of ABC294640. The GCS inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or GCS shRNA/siRNA knockdown facilitated ABC294640-induced ceramide production and lung cancer cell apoptosis. Reversely, forced overexpression of GCS reduced ABC294640's sensitivity, resulting in decreased ceramide accumulation and apoptosis induction in A549 cells. These findings provide further evidences to support that targeting SphK2 by ABC294640 may be a rational treatment option for lung cancer. Ceramide glucosylation inhibition may further sensitize lung cancer cells to ABC294640.
authors.affiliation: Department of Respiratory Medicine, The Third Affiliated Hospital, Soochow University, The First People's Hospital of Changzhou, Changzhou, China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Guan
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Yuan Y
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, The Third Affiliated Hospital, Soochow University, The First People's Hospital of Changzhou, Changzhou, China.
authors.forename: Tingzan
authors.initials: T
authors.lastname: Yan
authors.affiliation: Department of Respiratory Medicine, The Third Affiliated Hospital, Soochow University, The First People's Hospital of Changzhou, Changzhou, China. Electronic address: mdzhoujun918@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000072283:A549 Cells; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D000970:Antineoplastic Agents; D002518:Ceramides; D005964:Glucosyltransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C023246:ceramide glucosyltransferase; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase
keywords: ABC294640; Ceramide; Glucosylceramide synthase (GCS); Lung cancer; Sphingosine kinase 2 (SphK2)