Role of neutral ceramidase in colon cancer

Garcı́a-Barros, Mónica; Coant, Nicolas; Kawamori, Toshihiko; Wada, M.; Snider, Ashley J.; Truman, Jean‐Philip; Wu, Bill X.; Furuya, Hideki; Clarke, Christopher J.; Bialkowska, Agnieszka B.; Ghaleb, Amr M.; Yang, Vincent W.; Obeid, Lina M.; Hannun, Yusuf A.

doi:10.1096/fj.201600611r

Cited by 67 publications

(76 citation statements)

References 57 publications

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“…NCDase is highly abundant in intestinal tissues, and inhibition of NCDase resulted in ceramide-mediated apoptosis and autophagy in colon cancer cells and tumour xenograft mouse models 70 . Moreover, NCDase-null mice were protected from the development of AOM-induced colon cancer 70 .…”

Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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“…This study also demonstrated that inhibition of NC in a xenograft model delayed tumor growth and increased ceramide. Importantly, mice lacking NC treated with the pro-carcinogen azoxymethane were protected from tumor formation (Garcia-Barros et al, 2016). These results suggest that NC may emerge as a therapeutic target in colon cancer.…”

Section: Neutral Ceramidase (Asah2 Asah2b Asah2c)mentioning

confidence: 99%

Ceramidases, roles in sphingolipid metabolism and in health and disease

Coant

Sakamoto

Mao

et al. 2017

Advances in Biological Regulation

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203

146

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Over the past three decades, extensive research has been able to determine the biologic functions for the main bioactive sphingolipids, namely ceramide, sphingosine, and sphingosine 1-phosphate (S1P)(Hannun, 1996; Hannun et al., 1986; Okazaki et al., 1989). These studies have managed to define the metabolism, regulation, and function of these bioactive sphingolipids. This emerging body of literature has also implicated bioactive sphingolipids, particularly S1P and ceramide, as key regulators of cellular homeostasis. Ceramidases have the important role of cleaving fatty acid from ceramide and producing sphingosine, thereby controlling the interconversion of these two lipids. Thus far, five human ceramidases encoded by five different genes have been identified: acid ceramidase (AC), neutral ceramidase (NC), alkaline ceramidase 1 (ACER1), alkaline ceramidase 2 (ACER2), and alkaline ceramidase 3 (ACER3). These ceramidases are classified according to their optimal pH for catalytic activity. AC, which is localized to the lysosomal compartment, has been associated with Farber’s disease and is involved in the regulation of cell viability. Neutral ceramidase, which is localized to the plasma membrane and primarily expressed in the small intestine and colon, is involved in digestion, and has been implicated in colon carcinogenesis. ACER1 which can be found in the endoplasmic reticulum and is highly expressed in the skin, plays an important role in keratinocyte differentiation. ACER2, localized to the Golgi complex and highly expressed in the placenta, is involved in programed cell death in response to DNA damage. ACER3, also localized to the endoplasmic reticulum and the Golgi complex, is ubiquitously expressed, and is involved in motor coordination-associated Purkinje cell degeneration. This review seeks to consolidate the current knowledge regarding these key cellular players..

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“…62 RNAi targeting of ASAH2 in HT29 and HCT116 colon cancer cell lines increases ceramide, leading to 50% loss in viability in vitro and delayed xenograft growth in vivo. 63 In the AOM carcinogenesis model, ASAH2-deficient mice developed significantly fewer tumors with a 93% reduction in adenocarcinomas and an 82% decrease in total colon tumors compared with wild type mice. 63…”

Section: Ceramidasesmentioning

confidence: 96%

“…63 In the AOM carcinogenesis model, ASAH2-deficient mice developed significantly fewer tumors with a 93% reduction in adenocarcinomas and an 82% decrease in total colon tumors compared with wild type mice. 63…”

Section: Ceramidasesmentioning

confidence: 96%

Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

Camp

Patterson

Kester

et al. 2017

Cancer Biology & Therapy

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Therapy of colorectal cancer (CRC), especially a subset known as locally advanced rectal cancer, is challenged by progression and recurrence. Sphingolipids, a lipid subtype with vital roles in cellular function, play an important role in CRC and impact on therapeutic outcomes. In this review we discuss how dietary sphingolipids or the gut microbiome via alterations in sphingolipids influence CRC carcinogenesis. In addition, we discuss the expression of sphingolipid enzymes in the gastro-intestinal tract, their alterations in CRC, and the implications for therapy responsiveness. Lastly, we highlight some novel therapeutics that target sphingolipid signaling and have potential applications in the treatment of CRC. Understanding how sphingolipid metabolism impacts cell death susceptibility and drug resistance will be critical toward improving therapeutic outcomes.

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Role of neutral ceramidase in colon cancer

Cited by 67 publications

References 57 publications

Sphingolipid metabolism in cancer signalling and therapy

Sphingolipid metabolism in cancer signalling and therapy

Ceramidases, roles in sphingolipid metabolism and in health and disease

Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

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