Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells.
The tumor-associated microenvironment has been shown to protect tumor cells from treatment, and the extracellular matrix (ECM) is known to affect drug resistance as a key regulator of the tumor microenvironment. However, little is known about cell adhesion-mediated drug resistance (CAM-DR) due to cell-ECM contact in patients with oral squamous cell carcinoma (OSCC). In the present study, we evaluated the ECM molecule fibronectin (FN) using DNA microarray data obtained from parental and 5-FU-resistant OSCC cell lines. We investigated the effects of cell adhesion to FN on 5-FU resistance in OSCC cells and examined the activation of FN receptor β1 integrin-mediated survival regulators such as ILK, Akt and NF-κB. In addition, we investigated whether FNIII14, a 22-mer peptide derived from FN that potently prevents β1 integrin-mediated adhesion to FN, could overcome CAM-DR against 5-FU in OSCC cells and examined the activation of survival regulators and apoptosis-related molecules. Consequently, we obtained the following results. FN was extracellularly overexpressed in the 5-FU-resistant cells compared with that observed in the 5-FU-sensitive cells. Cell adhesion to FN enhanced 5-FU resistance and activated integrin-mediated ILK/Akt/NF-κB survival signaling in the 5-FU-resistant OSCC cells. Furthermore, the inhibition of cell adhesion to FN by FNIII14 enhanced chemosensitivity to 5-FU and apoptosis by suppressing ILK/Akt/NF-κB signaling in the 5-FU-resistant cells. These novel findings demonstrate that FN is a potentially useful biomarker and therapeutic target for improving the treatment of OSCC, particularly in the setting of 5-FU resistance.
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Yoshihiro
Y
Nakagawa
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Hideki
H
Nakayama
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Masashi
M
Nagata
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Ryoji
R
Yoshida
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Kenta
K
Kawahara
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Akiyuki
A
Hirosue
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Takuya
T
Tanaka
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Akira
A
Yuno
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Yuichiro
Y
Matsuoka
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Taku
T
Kojima
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Yoshihiro
Y
Yoshitake
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Akimitsu
A
Hiraki
Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-8556, Japan.
Masanori
M
Shinohara
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005109:Extracellular Matrix / Q000187:drug effects; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D000099200:Scaffold Protein ILK
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D005353:Fibronectins; D005472:Fluorouracil; D019012:Integrin beta1; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK