Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to s...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 123; no. 10; pp. 4344 - 4358
Main Authors:	Cheng, Joseph C., Bai, Aiping, Beckham, Thomas H., Marrison, S. Tucker, Yount, Caroline L., Young, Katherine, Lu, Ping, Bartlett, Anne M., Wu, Bill X., Keane, Barry J., Armeson, Kent E., Marshall, David T., Keane, Thomas E., Smith, Michael T., Jones, E. Ellen, Drake, Richard R., Bielawska, Alicja, Norris, James S., Liu, Xiang
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01.10.2013
Subjects:	Acid Ceramidase - antagonists & inhibitors Acid Ceramidase - genetics Acid Ceramidase - metabolism Amides - administration & dosage Amides - pharmacology Animals Biomedical research Cancer therapies Care and treatment Cell culture Cell Line, Tumor Enzyme Induction - radiation effects Enzymes Gene Expression Gene Expression Regulation, Neoplastic - radiation effects Genetic aspects Humans Hydrolases Injections, Intraperitoneal Ionizing radiation Kinases Male Mice Mice, Nude Neoplasm Recurrence, Local - enzymology Neoplasm Recurrence, Local - prevention & control Promoter Regions, Genetic Propanolamines - administration & dosage Propanolamines - pharmacology Properties Prostate cancer Prostatic Neoplasms - enzymology Prostatic Neoplasms - pathology Prostatic Neoplasms - radiotherapy Protein Binding Proteins Proto-Oncogene Proteins c-jun - metabolism Radiation therapy Radiation Tolerance Radiation-Sensitizing Agents - administration & dosage Radiation-Sensitizing Agents - pharmacology Radiotherapy Sphingolipids - metabolism Studies Transcription Factor AP-1 - metabolism Transcriptional Activation - radiation effects Tumors Xenograft Model Antitumor Assays United States
ISSN:	0021-9738, 1558-8238, 1558-8238
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Summary:	Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Authorship note: James S. Norris and Xiang Liu are co–senior authors.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI64791