Role of Acid Ceramidase in Resistance to FasL: Therapeutic Approaches Based on Acid Ceramidase Inhibitors and FasL Gene Therapy

Elojeimy, Saeed; Liu, Xiang; McKillop, John; El-Zawahry, Ahmed; Holman, David H.; Cheng, Jonathan Y; Meacham, William D.; Mahdy, Ayman; Saad, Antonio F.; Turner, Lorianne S.; Cheng, Joseph; Day, Terrence A.; Dong, Jian-Yun; Bielawska, Alicja; Hannun, Yusuf A.; Norris, James S.

doi:10.1038/sj.mt.6300167

Cited by 85 publications

(72 citation statements)

References 21 publications

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“…44,45 Furthermore, acid ceramidase inhibitors such as LCL204 are also being studied as new cancer therapies. 46 Since BEX2 has a significant effect on the survival and growth of breast cancer cells, such as their sensitivity to proapoptotic agents and the regulation of PP2A activity in these cells, BEX2 is a potential therapeutic target in breast cancer.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer

Naderi¹,

Liu²,

Bennett³

2010

Intl Journal of Cancer

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We have recently demonstrated that BEX2 is differentially expressed in primary breast tumors and BEX2 expression is required for the Nerve Growth factor inhibition of ceramide-induced apoptosis in breast cancer. In this study we investigate the functional role of BEX2 in the survival and growth of breast cancer cells. We demonstrate that BEX2 downregulation induces mitochondrial apoptosis and sensitizes breast cancer cells to the pro-apoptotic effects of ceramide, doxorubicin and staurosporine. In addition, BEX2 overexpression protects the breast cancer cells against mitochondrial apoptosis. We show that this effect of BEX2 is mediated through the modulation of Bcl-2 protein family, which involves the positive regulation of anti-apoptotic member Bcl-2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA. Moreover, our data suggests that BEX2 expression is required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of cyclin D1 and p21. To further support the significance of BEX2 in the pathogenesis of breast cancer we demonstrate that BEX2 overexpression is associated with a higher activation of the Bcl-2/NF-jB pathway in primary breast tumors. Furthermore, we show that BEX2 downregulation results in a higher expression and activity of protein phosphatase 2A. The modulation of protein phosphatase 2A, which is also known to mediate the cellular response to ceramide, provides a possible mechanism to explain the BEX2-mediated cellular effects. This study demonstrates that BEX2 has a significant role in the regulation of mitochondrial apoptosis and G1 cell cycle in breast cancer.

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Section: Cancer Cell Biologymentioning

confidence: 99%

BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer

Naderi¹,

Liu²,

Bennett³

2010

Intl Journal of Cancer

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“…While the characterization of aberrant, cancer-associated gene expression in tissues obtained for diagnosis versus noncancerous tissues is a prominent arena of research (39), the response of tumors to therapy also represents a critical avenue of investigation (22). Work by this group and others has demonstrated that the ceramide-metabolizing enzyme, acid ceramidase (AC), can play an important role in resistance to anticancer therapies (40)(41)(42)(43)(44)(45)(46)(47), including IR (26,36,48,49). In this report, we evaluated transcriptional activation of AC in PCa cells treated with radiation.…”

Section: Introductionmentioning

confidence: 99%

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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“…Because Cer hydrolysis is the major pathway for SPH generation (45), ASAH1 plays a key role in regulating cellular homeostasis by controlling the Cer/SPH/S1P balance within the cell. In addition, the aberrant expression of ASAH1 in various human cancers (46 -49), including breast cancer (50), prompted the emergence of this enzyme as a potential target for chemotherapy (48,51,52). Inhibitors of ASAH1 such as B13 and LCL464 were shown to cause Cer accumulation and prevent tumor growth (51,53).…”

mentioning

confidence: 99%

Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression

Lucki

Sewer

2011

Journal of Biological Chemistry

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Sphingolipid metabolites, such as ceramide (Cer), sphingosine (SPH), and sphingosine 1-phosphate (S1P), contribute to multiple aspects of carcinogenesis including cell proliferation, migration, angiogenesis, and tumor resistance. The cellular balance between Cer and S1P levels, for example, is an important determinant of cell fate, with the former inducing apoptosis and the later mitogenesis. Acid ceramidase (ASAH1) plays a pivotal role in regulating the intracellular concentration of these two metabolites by hydrolyzing Cer into SPH, which is rapidly phosphorylated to form S1P. Genistein is a phytoestrogen isoflavone that exerts agonist and antagonist effects on the proliferation of estrogen-dependent MCF-7 cells in a dose-dependent manner, primarily as a ligand for estrogen receptors. Genistein can also activate signaling through GPR30, a G-protein-coupled cell surface receptor. Based on the relationship between bioactive sphingolipids and tumorigenesis, we sought to determine the effect of genistein on ASAH1 transcription in MCF-7 breast cancer cells. We show herein that nanomolar concentrations of genistein induce ASAH1 transcription through a GPR30-dependent, pertussis toxin-sensitive pathway that requires the activation of c-Src and extracellular signal regulated kinase 1/2 (ERK1/2). Activation of this pathway promotes histone acetylation and recruitment of phospho-estrogen receptor ␣ and specificity protein-1 to the ASAH1 promoter, ultimately culminating in increased ceramidase activity. Finally, we show that genistein stimulates cyclin B2 expression and cell proliferation in an ASAH1-dependent manner. Collectively, these data identify a mechanism through which genistein promotes sphingolipid metabolism and support a role for ASAH1 in breast cancer cell growth.

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Role of Acid Ceramidase in Resistance to FasL: Therapeutic Approaches Based on Acid Ceramidase Inhibitors and FasL Gene Therapy

Cited by 85 publications

References 21 publications

BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer

BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer

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

Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression

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