Role of acid ceramidase in resistance to fasL

Therapeutic approaches based on acid ceramidase inhibitors and fasL gene therapy

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

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Head and neck squamous cell cancers (HNSCC) are particularly aggressive and are resistant to many forms of treatment. Ceramide metabolism has been shown to play an important role in cancer progression and cancer resistance to therapy in many tumor models, including HNSCC. Here, we study the role of the ceramide-metabolizing enzyme acid ceramidase (AC) in therapeutic responses in HNSCC. First, we show that AC is over-expressed in 70% of head and neck squamous cell tumors compared with normal tissues, suggesting that this enzyme may play an important role in facilitating HNSCC growth. Next, comparison of three HNSCC cell lines with low, medium, and high levels of AC reveals an inverse correlation between the levels of AC and their response to exogenous C-6-ceramide. Furthermore, over-expression of AC in SCC-1 cells increased resistance to Fas-induced cell killing. Conversely, down-regulation of AC using specific AC small interfering RNA (siRNA) sensitized the SCC-1 cancer cell line to Fas-induced apoptosis. Finally, we show that the AC inhibitor LCL 204 can sensitize HNSCC cell lines to Fas-induced apoptosis both in vitro and in a xenograft model in vivo, suggesting that the combination of FasL gene therapy and LCL 204 may become a new treatment option for advanced-stage head and neck cancer.

Original languageEnglish (US)
Pages (from-to)1259-1263
Number of pages5
JournalMolecular Therapy
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

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Acid Ceramidase
Squamous Cell Neoplasms
Genetic Therapy
Head and Neck Neoplasms
Head
Ceramides
Therapeutics
Neoplasms
Cell Line
Apoptosis
Enzymes
Heterografts
Small Interfering RNA
Neck
Down-Regulation
Epithelial Cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Elojeimy, S., Liu, X., Mckillop, J. C., El-Zawahry, A. M., Holman, D. H., Cheng, J. Y., ... Norris, J. S. (2007). Role of acid ceramidase in resistance to fasL: Therapeutic approaches based on acid ceramidase inhibitors and fasL gene therapy. Molecular Therapy, 15(7), 1259-1263. https://doi.org/10.1038/sj.mt.6300167

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 C.; El-Zawahry, Ahmed M.; Holman, David H.; Cheng, Jonathan Y.; Meacham, William D.; Mahdy, Ayman E.M.; Saad, Antonio; Turner, Lorianne S.; Cheng, Joseph; A Day, Terrence; Dong, Jian Yun; Bielawska, Alicja; Hannun, Yusuf A.; Norris, James Scott.

In: Molecular Therapy, Vol. 15, No. 7, 01.07.2007, p. 1259-1263.

Research output: Contribution to journalArticle

Elojeimy, S, Liu, X, Mckillop, JC, El-Zawahry, AM, Holman, DH, Cheng, JY, Meacham, WD, Mahdy, AEM, Saad, A, Turner, LS, Cheng, J, A Day, T, Dong, JY, Bielawska, A, Hannun, YA & Norris, JS 2007, 'Role of acid ceramidase in resistance to fasL: Therapeutic approaches based on acid ceramidase inhibitors and fasL gene therapy', Molecular Therapy, vol. 15, no. 7, pp. 1259-1263. https://doi.org/10.1038/sj.mt.6300167
Elojeimy, Saeed ; Liu, Xiang ; Mckillop, John C. ; El-Zawahry, Ahmed M. ; Holman, David H. ; Cheng, Jonathan Y. ; Meacham, William D. ; Mahdy, Ayman E.M. ; Saad, Antonio ; Turner, Lorianne S. ; Cheng, Joseph ; A Day, Terrence ; Dong, Jian Yun ; Bielawska, Alicja ; Hannun, Yusuf A. ; Norris, James Scott. / Role of acid ceramidase in resistance to fasL : Therapeutic approaches based on acid ceramidase inhibitors and fasL gene therapy. In: Molecular Therapy. 2007 ; Vol. 15, No. 7. pp. 1259-1263.
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