Deguelin induces both apoptosis and autophagy in cultured head and neck squamous cell carcinoma cells.
Head and neck squamous cell carcinoma (HNSCC) represents more than 5% of all cancers diagnosed annually in United States and around the world. Despite advances in the management of patients with this disease, the survival has not been significantly improved, and the search for potential alternative therapies is encouraging. Here we demonstrate that deguelin administration causes a significant HNSCC cell death. Deguelin induces both cell apoptosis and autophagy by modulating multiple signaling pathways in cultured HNSCC cells. Deguelin inhibits Akt signaling, and down-regulates survivin and cyclin-dependent kinase 4 (Cdk4) expressions, by disrupting their association with heat shock protein-90 (Hsp-90). Deguelin induces ceramide production through de novo synthase pathway to promote HNSCC cell death. Importantly, increased ceramide level activates AMP-activated protein kinase (AMPK), which then directly phosphorylates Ulk1 and eventually leads to cell autophagy. We found that a low dose of deguelin sensitized HNSCC cells to 5-FU. Finally, using a nude mice Hep-2 xenograft model, we also showed a significant anti-tumor ability of deguelin in vivo. Together, we suggest that deguelin may represent a novel and effective chemo-agent against HNSCC.
Department of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Yan-li
YL
Yang
Chao
C
Ji
Zhi-gang
ZG
Bi
Chun-cheng
CC
Lu
Rong
R
Wang
Bing
B
Gu
Lei
L
Cheng
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012402:Rotenone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D000077022:Survivin; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002518:Ceramides; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D012402:Rotenone; D051057:Proto-Oncogene Proteins c-akt; D051358:Cyclin-Dependent Kinase 4; D055372:AMP-Activated Protein Kinases; C107676:deguelin; D005472:Fluorouracil