The roles of JNK1 and Stat3 in the response of head and neck cancer cell lines to combined treatment with all-trans-retinoic acid and 5-fluorouracil.
We have used a combination of vitamin A (all-trans-retinyl palmitate), 5-fluorouracil (5-FU) and radiation to treat human head and neck squamous cell carcinoma (HNSCC). This chemoradiotherapy is called "FAR therapy." In this study we examined the effects of all-trans-retinoic acid (ATRA), the active metabolite of vitamin A, and ATRA plus 5-FU on two HNSCC cell lines (YCU-N861 and YCU-H891) to gain insight into the molecular mechanisms of FAR therapy. ATRA at 1 mM (the order of concentration found in HNSCC tumors treated with FAR therapy) inhibited cell proliferation and caused G1 cell cycle arrest in both cell lines. This was associated with a decrease in cyclin D1, an increase in p27(Kip1) and a reduction in the hyperphosphorylated form of retinoblastoma protein (pRB). With YCU-N861 cells, ATRA also caused a decrease in Bcl-2 and Bcl-X(L) and an increase in Bax. Both ATRA and 5-FU activated c-Jun N-terminal kinase (JNK) 1 and the combination of both agents resulted in additive or synergistic activation of JNK1, and also enhanced the induction of apoptosis. The YCU-H891 cells, in which the epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription 3 (Stat3) pathway is constitutively activated, were more resistant to treatments with ATRA, 5-FU and the combination of both agents than YCU-N861 cells. A dominant negative Stat3 construct strongly enhanced the cellular sensitivity of this cell line to 5-FU but not to ATRA. In addition there is evidence that activation of Stat3 is associated with cellular resistance to radiation in HNSCC. Therefore, the addition to FAR therapy of agents that inhibit activation of the Stat3 pathway may enhance the clinical response of patients with HNSCC to FAR therapy.
Masuda
Muneyuki
M
Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Kyushu University, Fukuoka 812-0052, Japan. masuda@cuccfa.ccc.columbia.edu
Toh
Satoshi
S
Koike
Koji
K
Kuratomi
Yuichiro
Y
Suzui
Masumi
M
Deguchi
Atsuko
A
Komiyama
Sohtaro
S
Weinstein
I Bernard
IB
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; D014212:Tretinoin; D066246:ErbB Receptors; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D005472:Fluorouracil