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Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse
Joseph C. Cheng, … , James S. Norris, Xiang Liu
Joseph C. Cheng, … , James S. Norris, Xiang Liu
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4344-4358. https://doi.org/10.1172/JCI64791.
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Research Article Oncology

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

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Abstract

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.

Authors

Joseph C. Cheng, Aiping Bai, Thomas H. Beckham, S. Tucker Marrison, Caroline L. Yount, Katherine Young, Ping Lu, Anne M. Bartlett, Bill X. Wu, Barry J. Keane, Kent E. Armeson, David T. Marshall, Thomas E. Keane, Michael T. Smith, E. Ellen Jones, Richard R. Drake Jr., Alicja Bielawska, James S. Norris, Xiang Liu

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Figure 8

Radiosensitization of PCa IR via AC inhibition.

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Radiosensitization of PCa IR via AC inhibition.
(A) Protein expression i...
(A) Protein expression in PPC-1 cells treated with AC small molecule inhibitor LCL521 (5 μM, 24 hours). Mean densitometry of normalized AC expression is shown. (B) 72-hour-dose responses of 22Rv1, DU 145, PPC-1, and WPMY-1 cell lines to LCL521 exposure. (C) Isobologram of LCL521 and IR combination therapy based on PPC-1 cell treatment for 8 days (single IR fraction at day 0; LCL521 treatment at days 0 and 4). Solid line represents theoretical line of additivity ± SD (dashed lines). (D) Ester bond hydrolysis of prodrug LCL521 into LCL522 and secondary ester bond hydrolysis into the active AC inhibitor, B13, in PPC-1 xenografts 6 hours after intraperitoneal administration (75 mg/kg). Subcutaneous PPC-1 xenografts grown on the flanks of athymic nu/nu mice were subjected to 6 × 5 Gy fractions of focal γ irradiation (red triangles) in combination with LCL521 (75 mg/kg, i.p. injection) or cremophor EL (vehicle control). (E) Xenograft volumes and (F) overall survival were monitored, and representative xenografts are depicted at day 108; n per group noted parenthetically.

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