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

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.

Expression of Ceramide Synthase 6 Transcriptionally Activates Acid Ceramidase in a c-Jun N-terminal Kinase (JNK)-dependent Manner

“…4, A-C). The increase in acid ceramidase following CerS6 expression was not unique to HT29 cells and was also observed in SW620 colon cancer cells that overexpress CerS6 (previously described in (3)) as well as in PPC1 prostate cancer cells transduced with an adenovirus expressing CerS6 (34). These data suggest that the increase in acid ceramidase following CerS6 expression is not a cell line or tissue-specific response.…”

“…This is in contrast to prostate cancer cells in which elevated acid ceramidase expression has been associated with apoptosis resistance and relapse following radiation therapy (34,39). It was previously observed that an increase in acid ceramidase, which is a lysosomal enzyme, resulted in elevated lysosomal density and increased levels of autophagy (40).…”

“…Sphingosine holds a unique position in sphingolipid metabolism in that it can be further metabolized to sphingosine-1-phosphate (S1P) by sphingosine kinases or serve as a substrate for ceramide synthases in the salvage pathway (10). Irradiation of prostate cancer cells increased the pro-apoptotic sphingolipids ceramide and sphingosine but also elevated sphingosine-1-phosphate (S1P), indicating that sphingosine was further metabolized by sphingosine kinases (34). In contrast, in HT29 colon cancer cells intracellular S1P generation is greatly diminished upon CerS6 expression (Fig.…”

“…Ceramide stress has been shown to activate the JNK pathway (31-33) and more recently it has been shown that radiation-induced ceramide stress and subsequent up-regulation of acid ceramidase occurs in an AP-1-dependent manner (34). Therefore, we treated HTCerS6 cells with the JNK inhibitor SP600125 or curcumin, a natural compound with anti-tumor activity that has been shown to directly interfere with DNA binding at the AP-1 transcription factor (35,36), and examined the impact on phosphorylation of c-jun and acid ceramidase expression.…”

IL-17 induces radiation resistance of B lymphoma cells by suppressing p53 expression and thereby inhibiting irradiation-triggered apoptosis

“…21 The present study has revealed that, after irradiation, k1106 lymphoma cells express IL-6; the latter induces IL-17 expression in Tregs. IL-17 suppressed the expression of p53 in k1106 cells which compromised apoptosis, thus attenuating the effect of irradiation on inducing apoptosis in k1106 cells.…”