Role of acid ceramidase in resistance to FasL: therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy.

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.

• Authors: Saeed Elojeimy, Xiang Liu, John C McKillop, Ahmed M El-Zawahry, David H Holman, Jonathan Y Cheng, William D Meacham, Ayman Em Mahdy, Antonio F Saad, Lorianne S Turner, Joseph Cheng, Terrence A Day, Jian-Yun Dong, Alicja Bielawska, Yusuf A Hannun, James Scott Norris
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 15 Issue 7 Pg. 1259-63 (Jul 2007) ISSN: 1525-0024 [Electronic] United States
• PMID: 17426710 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ceramides
• Enzyme Inhibitors
• Fas Ligand Protein
• RNA, Small Interfering
• Galactosylgalactosylglucosylceramidase

Topics

• Animals
• Cell Line, Tumor
• Cell Survival
• Ceramides (metabolism)
• Down-Regulation
• Enzyme Inhibitors (pharmacology)
• Fas Ligand Protein (genetics, metabolism)
• Female
• Galactosylgalactosylglucosylceramidase (antagonists & inhibitors, metabolism)
• Gene Expression Regulation, Neoplastic
• Genetic Therapy
• Head and Neck Neoplasms (genetics, metabolism)
• Humans
• Mice
• Mice, Nude
• RNA, Small Interfering (genetics)
• Sensitivity and Specificity
• Xenograft Model Antitumor Assays