Diversity and Complexity of Ceramide Generation After Exposure of Jurkat Leukemia Cells to Irradiation

Ardail, Dominique; Maalouf, Mira; Boivin, Anthony; Chapet, O.; Bodennec, Jacques; Rousson, Robert; Rodriguez-Lafrasse, Claire

doi:10.1016/j.ijrobp.2008.11.033

Cited by 16 publications

(17 citation statements)

References 45 publications

(73 reference statements)

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“…Ultimately, the late phase generation of ceramide depends on the DNA damage machinery, supporting earlier results involving the ATM gene, and CerS-mediated ceramide represents the rate-limiting apoptotic step of radiation-induced cell death. Similar biphasic patterns of ceramide generation were demonstrated in Jurkat leukemia cells (Ardail et al, 2009). The dependence of late phase ceramide generation on the earlier phase was supported by this study which found sphingomyelin-sourced ceramide in plasma membrane lipid rafts only 15 min postirradiation; a second peak in ceramide 4 h later was evidenced at the mitochondria via ASMase targeting of this organelle.…”

Section: Sphingolipids and Radiation Therapysupporting

confidence: 70%

Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies

Beckham

Cheng

Marrison

et al. 2013

Advances in Cancer Research

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Non-surgical therapies for human malignancies must negotiate complex cell signaling pathways to impede cancer cell growth, ideally promoting death of cancer cells while sparing healthy tissue. For most of the past half century, medical approaches for treating cancer have relied primarily on cytotoxic chemotherapeutics that interfere with DNA replication and cell division, susceptibilities of rapidly dividing cancer cells. As a consequence, these therapies exert considerable cell stress, promoting the generation of ceramide through de novo synthesis and recycling of complex glycosphingolipids and sphingomyelin into apoptotic ceramide. Radiotherapy of cancer exerts similar geno- and cytotoxic cell stresses, and generation of ceramide following ionizing radiation therapy is a well-described feature of radiation-induced cell death. Emerging evidence now describes sphingolipids as mediators of death in response to newer targeted therapies, cementing ceramide generation as a common mechanism of cell death in response to cancer therapy. Many studies have now shown that dysregulation of ceramide accumulation—whether by reduced generation or accelerated metabolism—is a common mechanism of resistance to standard cancer therapies. The aims of this chapter will be to discuss described mechanisms of cancer resistance to therapy related to dysregulation of sphingolipid metabolism and to explore clinical and preclinical approaches to interdict sphingolipid metabolism to improve outcomes of standard cancer therapies.

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Section: Sphingolipids and Radiation Therapysupporting

confidence: 70%

Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies

Beckham

Cheng

Marrison

et al. 2013

Advances in Cancer Research

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“…A substantive literature identifies mitochondrial ceramide elevation preceding MOMP for a variety of distinct stresses [10], [11], [12], [13], [14]. Furthermore, in isolated mitochondria ceramide and recombinant Bax act coordinately to release cytochrome C [15], [16], [17].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Ceramide-Rich Macrodomains Functionalize Bax upon Irradiation

et al. 2011

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BackgroundEvidence indicates that Bax functions as a “lipidic” pore to regulate mitochondrial outer membrane permeabilization (MOMP), the apoptosis commitment step, through unknown membrane elements. Here we show mitochondrial ceramide elevation facilitates MOMP-mediated cytochrome c release in HeLa cells by generating a previously-unrecognized mitochondrial ceramide-rich macrodomain (MCRM), which we visualize and isolate, into which Bax integrates.Methodology/Principal FindingsMCRMs, virtually non-existent in resting cells, form upon irradiation coupled to ceramide synthase-mediated ceramide elevation, optimizing Bax insertion/oligomerization and MOMP. MCRMs are detected by confocal microscopy in intact HeLa cells and isolated biophysically as a light membrane fraction from HeLa cell lysates. Inhibiting ceramide generation using a well-defined natural ceramide synthase inhibitor, Fumonisin B1, prevented radiation-induced Bax insertion, oligomerization and MOMP. MCRM deconstruction using purified mouse hepatic mitochondria revealed ceramide alone is non-apoptogenic. Rather Bax integrates into MCRMs, oligomerizing therein, conferring 1–2 log enhanced cytochrome c release. Consistent with this mechanism, MCRM Bax isolates as high molecular weight “pore-forming” oligomers, while non-MCRM membrane contains exclusively MOMP-incompatible monomeric Bax.Conclusions/SignificanceOur recent studies in the C. elegans germline indicate that mitochondrial ceramide generation is obligate for radiation-induced apoptosis, although a mechanism for ceramide action was not delineated. Here we demonstrate that ceramide, generated in the mitochondrial outer membrane of mammalian cells upon irradiation, forms a platform into which Bax inserts, oligomerizes and functionalizes as a pore. We posit conceptualization of ceramide as a membrane-based stress calibrator, driving membrane macrodomain organization, which in mitochondria regulates intensity of Bax-induced MOMP, and is pharmacologically tractable in vitro and in vivo.

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“…Canonical pathways of cell death would include the well-characterized pathway of de novo ceramide accumulation subsequent to irradiation supported by the findings of the Kolesnick group and others (23,38,51,71,72). The Kolesnick group characterized this de novo ceramide generation pathway in HeLa cells as dependent on CerS5/6 activation (70).…”

Section: Discussionmentioning

confidence: 85%

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

et al. 2013

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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.

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Diversity and Complexity of Ceramide Generation After Exposure of Jurkat Leukemia Cells to Irradiation

Cited by 16 publications

References 45 publications

Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies

Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies

Mitochondrial Ceramide-Rich Macrodomains Functionalize Bax upon Irradiation

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

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