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Overcoming Resistance to C-Rays in Squamous Carcinoma Cells by Poly-Drug Elevation of Ceramide Levels

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Overcoming Resistance to C-Rays in Squamous Carcinoma Cells by Poly-Drug Elevation of Ceramide Levels Oncogene (2004) 23, 2703–2715 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc Overcoming resistance to c-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels Gersende Alphonse1, Clara Bionda1, Marie-The´ re` se Aloy1, Dominique Ardail1, Robert Rousson1 and Claire Rodriguez-Lafrasse*,1 1Department of Biochemistry, INSERM U189, Lyon-Sud Medical School, BP12, 69921 Oullins Cedex, France. Recent strategies to sensitize radioresistant tumours of pro- or antiapoptotic proteins (Solary et al., 2001), are based on combining c-irradiation with inducers whereas, previously, cancer therapies have usually of apoptosis. We report that the combination of involved nonselective agents that induce DNA damage three inhibitors of sphingolipid metabolism, DL-threo-1- or interfere with DNA repair. Shifting the balance to the phenyl-2-decanoylamino-3-morpholino-1-propanol.HCl(DL- proapoptotic pathway may increase apoptotic cell kill- PDMP) þ imipramine7D-erythro-2-(N-myristoylamino)- ing and represents a potential improvement in cancer 1-phenyl-1-propanol (D-MAPP), with 10-Gy irradiation therapy. triggers both mitotic and apoptotic killing in radio- Several studies have attempted to overexpress the resistant SQ20B squamous carcinoma cells. In these cells, proapoptotic proteins involved in the formation of apoptosis is defective due to a lack of ceramide generation apoptosomes, such as Apaf-1 and caspase-9, which led upstream, which cannot be explained by sphingomyelinase to a clear increase in the radiosensitivity of U-373MG (neutral and acidic) deficiency or rapid derivation to the glioma cells (Shinoura et al., 2001). Other approaches, sphingolipid pathway. We present evidence of a functional like the overexpression of Bax (Lee et al., 1999; Lin et al., transduction death pathway when ceramide generation is 2001) or p21 WAF1/CIP1 antisense oligonucleotides restored, which involves the mitochondrial-mediated path- (Kokunai et al., 2001), also enhanced radiation-induced way coupled to alterations in redox status and to executive apoptosis. caspases activation. The poly-drug treatment restored It has been proposed that ceramide is a proapoptotic apoptosis to levels similar to those observed in radio- lipidic messenger, involved in the response to various sensitive SCC61squamous carcinoma cells. Simultaneous stimuli in a variety of normal and neoplastic cells (Perry, exposure to c-irradiation and poly-drug treatment acted 1999; Kolesnick and Fuks, 2003). In Jurkat leukaemia synergistically in SQ20B cells to produce a marked cells and SCC61 squamous carcinoma cells sensitive to increase in both mitochondrial dysfunction and caspase anti-Fas and g-irradiation, we demonstrated that cleavage, which led to a 7.8-fold increase in apoptosis ceramide is a determining factor in the commitment within 48 h, relative to irradiated cells. Moreover, the phase of apoptosis (Rodriguez-Lafrasse et al., 2001; results suggest that the ceramide released by irradiation or Alphonse et al., 2002). Ceramide acts upstream from poly-drug treatment converges upon common cellular and conveys the apoptotic signal to the mitochondria, targets. Modulation of endogenous ceramide levels by leading to the subsequent activation of executive inhibitors of sphingolipid metabolism may represent a new caspases. In resistant SQ20B adenocarcinoma cells, the cellular target for the sensitization of radioresistant lack of ceramide generation in response to both anti-Fas tumours to c-ray therapy. and g-irradiation makes the whole pathway ineffective Oncogene (2004) 23, 2703–2715. doi:10.1038/sj.onc.1207357 and leads to radioresistance (Alphonse et al., 2002). Published online 29 March 2004 Several works have also correlated defective ceramide generation or signalling with resistance to radiation- Keywords: SQ20B cells; SCC61 cells; g-irradiation; induced apoptosis (Chmura et al., 1997a, b; Bruno et al., apoptosis; inhibitors of sphingolipid metabolism 1998; Sautin et al., 2000). Moreover, Selzner et al. (2001) demonstrated that ceramide levels are reduced by more than 50% in human colon tumours relative to those of healthy colon mucosa collected from the same patients. Introduction In a recent study, Riboni et al. (2002) demonstrated an inverse correlation between the malignant progression New therapeutic strategies attempt to amplify or restore of human astrocytomas (low- and high-grade tumours) the apoptotic death pathway by targeting the expression and the ceramide content measured in surgical speci- mens. They also found that low ceramide levels, which confer rapid growth and apoptotic-resistant features to *Correspondence: C Rodriguez-Lafrasse; tumours, were associated with low patient survival. That E-mail: [email protected] Received 30 April 2003; revised 7 November 2003; accepted 12 study thus supports the potential benefits of ceramide- November 2003 based chemotherapy. Overcoming radioresistance by ceramide generation G Alphonse et al 2704 Therefore, manipulation of ceramide levels may be Results particularly relevant in the treatment of cancer (Radin, 2003), and more specifically in amplifying the efficiency Similar enzymatic activities of neutral and acid of radiotherapy. This was previously achieved either by sphingomyelinases, and glucosylceramide synthase in the addition of short-chain or natural ceramide to SQ20B and SCC61 cells in response to 10-Gy irradiation tumour cells (Sautin et al., 2000; Lozano et al., 2001; We first verified that the lack of ceramide generation in Selzner et al., 2001, Kimura et al., 2003) or by the addition of chemical agents that interfere with its radioresistant SQ20B cells does not result from enzy- matic dysregulation. The activities of three enzymes metabolism in cell cultures or in xenografts in nude implicated in the metabolism of ceramide were measured mice. For instance, Chmura et al. (1997a) reversed in SQ20B cells between 1 and 24 h after irradiation and the radioresistance of the SQ20B tumour model compared with those of radiosensitive SCC61 cells. The in vitro and in vivo by increasing sphingomyelinase total cellular content of sphingosine, glucosylceramide, activity by the addition of chelerythrine. Raisova and sialic acid were also determined in SQ20B cells. et al. (2002) increased the ceramide content and The basal levels of neutral sphingomyelinase activity induced apoptosis in HaCaT keratinocytes and human were very similar in the radioresistant and radiosensitive melanoma cells by the addition of a ceramidase cell lines (Figure 1). A dose of 10-Gy irradiation induced inhibitor. We previously used a combination of three different a gradual increase in neutral sphingomyelinase activity from 8 to 24 h in both cell lines (P 0.05). No significant inhibitors of sphingolipid metabolism, DL-threo-1- o activation of acid sphingomyelinase activity was ob- phenyl-2-decanoylamino-3-morpholino-1-propanol. HCl served between 1 and 24 h after irradiation in either cell (DL-PDMP) (a specific inhibitor of glucosylceramide line. Basal levels of this enzyme were 5.6470.44 mkat/mg synthase), D-erythro-2-(N-myristoylamino)-1-phenyl-1- protein in the radioresistant cell line, and threefold propanol (D-MAPP) (an inhibitor of ceramidase), and lower in the radiosensitive cell line. No significant imipramine (an amphiphilic amine that disturbs lipid variation in glucosylceramide synthase activity was turnover in biological membranes), to amplify the observed after irradiation in either cell line. However, endogenous ceramide signal in lymphoid cell lines the basal level of this enzyme was higher in the derived from leukaemic, Niemann-Pick A, or normal subjects (Rodriguez-Lafrasse et al., 2002). We demon- radiosensitive SCC61 cells. Furthermore, the total cellular content of glucosylceramide, sphingosine (which strated that endogenously formed ceramide triggers reflects ceramidase activity), and sialic acid (which time- and concentration-dependent apoptotic cell death through the induction of mitochondrial injury reflects cellular ganglioside content) did not differ between control and irradiated SQ20B cells (Figure 2). and the activation of the caspase pathway. In this study, Taken together, these results demonstrate that the we take advantage of this pharmacological model to lack of ceramide release in the radioresistant SQ20B cell overcome the radioresistant phenotype of SQ20B line in response to 10-Gy irradiation did not result from squamous carcinoma cells. We studied the death a deficit in sphingomyelinase activity as measured under response of this SQ20B cell line (SF2: 0.82) and also in vitro conditions, from highly stimulated glucosylcer- of SCC61 cells (SF2: 0.36), a radiosensitive control cell amide activity, or from rapid derivation to the line derived from the same histological type, to the sphingolipid pathway. combined effects of 10-Gy irradiation and the combined poly-drug, DL-PDMP þ imipramine7D-MAPP. We present evidence for the usefulness of generating Radioresistance of SQ20B cells does not result from intracellular ceramide by a poly-association of inhibitors neutral sphingomyelinase inhibition by elevated of sphingolipid metabolism to potentiate the cytotoxi- glutathione levels city of radiotherapy in resistant tumours. This proceeds through the activation of both clonogenic and apoptotic As basal glutathione levels were higher in resistant death, which were not detectable in the response of SQ20B cells than in SCC61 cells (Alphonse et al., 2002), SQ20B cells to
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