title: Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer.
abstract: Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Ayman E M
authors.initials: AE
authors.lastname: Mahdy
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Saeed
authors.initials: S
authors.lastname: Elojeimy
authors.forename: William D
authors.initials: WD
authors.lastname: Meacham
authors.forename: Lorianne S
authors.initials: LS
authors.lastname: Turner
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gault
authors.forename: Alex S
authors.initials: AS
authors.lastname: McPherson
authors.forename: Nicole
authors.initials: N
authors.lastname: Garcia
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Beckham
authors.forename: Antonio
authors.initials: A
authors.lastname: Saad
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Keane
authors.forename: Mohhammed I
authors.initials: MI
authors.lastname: Taha
authors.forename: Hisham M
authors.initials: HM
authors.lastname: Hammouda
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009226:Myristates / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000528:radiation effects*; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D055573:Acid Ceramidase; D002518:Ceramides; D004791:Enzyme Inhibitors; D009226:Myristates; D017239:Paclitaxel; D017853:Phosphotransferases (Alcohol Group Acceptor); D011412:Propanolamines; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D013110:Sphingosine; D000099157:Sphingosine Kinase; C539749:2-N-(tetradecylamino)-1-phenyl-1,3-propanediol