Role of acid ceramidase in resistance to FasL: therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy.
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.
Elojeimy
Saeed
S
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
Liu
Xiang
X
McKillop
John C
JC
El-Zawahry
Ahmed M
AM
Holman
David H
DH
Cheng
Jonathan Y
JY
Meacham
William D
WD
Mahdy
Ayman Em
AE
Saad
Antonio F
AF
Turner
Lorianne S
LS
Cheng
Joseph
J
A Day
Terrence
T
Dong
Jian-Yun
JY
Bielawska
Alicja
A
Hannun
Yusuf A
YA
Norris
James Scott
JS
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D002517:Galactosylgalactosylglucosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics; D012680:Sensitivity and Specificity; D023041:Xenograft Model Antitumor Assays
D002518:Ceramides; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D002517:Galactosylgalactosylglucosylceramidase