title: Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.
abstract: Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: McNaughton
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide SA 5000, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Pitman
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide SA 5000, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D000970:Antineoplastic Agents; D010088:Oxidoreductases; D017853:Phosphotransferases (Alcohol Group Acceptor); D046988:Proteasome Endopeptidase Complex; D011725:Pyridines; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C108138:dihydroceramide desaturase
keywords: dihydroceramide desaturase; growth arrest; prostate cancer; sphingosine 1-phosphate; sphingosine kinase