title: Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma.
abstract: Sphingosine kinase (SPHK) is overexpressed by a variety of cancers, and its phosphorylation of sphingosine results in accumulation of sphingosine-1-phosphate (S1P) and activation of antiapoptotic signal transduction. Existing data indicate a role for S1P in viral pathogenesis, but roles for SPHK and S1P in virus-associated cancer progression have not been defined. Rare pathologic variants of diffuse large B-cell lymphoma arise preferentially in the setting of HIV infection, including primary effusion lymphoma (PEL), a highly mortal tumor etiologically linked to the Kaposi's sarcoma-associated herpesvirus (KSHV). We have found that ABC294640, a novel clinical-grade small molecule selectively targeting SPHK (SPHK2 >> SPHK1), induces dose-dependent caspase cleavage and apoptosis for KSHV(+) patient-derived PEL cells, in part through inhibition of constitutive signal transduction associated with PEL cell proliferation and survival. These results were validated with induction of PEL cell apoptosis using SPHK2-specific siRNA, as well as confirmation of drug-induced SPHK inhibition in PEL cells with dose-dependent accumulation of proapoptotic ceramides and reduction of intracellular S1P. Furthermore, we demonstrate that systemic administration of ABC294640 induces tumor regression in an established human PEL xenograft model. Complimentary ex vivo analyses revealed suppression of signal transduction and increased KSHV lytic gene expression within drug-treated tumors, with the latter validated in vitro through demonstration of dose-dependent viral lytic gene expression within PEL cells exposed to ABC294640. Collectively, these results implicate interrelated mechanisms and SPHK2 inhibition in the induction of PEL cell death by ABC294640 and rationalize evaluation of ABC294640 in clinical trials for the treatment of KSHV-associated lymphoma.
authors.affiliation: Corresponding Author: Chris Parsons, Suite 712, Louisiana Cancer Research Center, 1700 Tulane Avenue, New Orleans, LA 70112. cpars1@lsuhsc.edu.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.forename: Jimena
authors.initials: J
authors.lastname: Trillo-Tinoco
authors.forename: Can
authors.initials: C
authors.lastname: Senkal
authors.forename: Wenxue
authors.initials: W
authors.lastname: Wang
authors.forename: Tom
authors.initials: T
authors.lastname: Reske
authors.forename: Karlie
authors.initials: K
authors.lastname: Bonstaff
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodriguez
authors.forename: Erik
authors.initials: E
authors.lastname: Flemington
authors.forename: Christina
authors.initials: C
authors.lastname: Voelkel-Johnson
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.forename: Chris
authors.initials: C
authors.lastname: Parsons
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000472:pathogenicity; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D008246:Lysophospholipids / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide