Resveratrol Targets Urokinase-Type Plasminogen Activator Receptor Expression to Overcome Cetuximab-Resistance in Oral Squamous Cell Carcinoma

• Published in: Scientific reports 2019-08, Vol.9 (1), p.12179-13, Article 12179
• Main Authors: Uzawa, Katsuhiro, Amelio, Antonio L., Kasamatsu, Atsushi, Saito, Tomoaki, Kita, Akihiro, Fukamachi, Megumi, Sawai, Yuki, Toeda, Yuriko, Eizuka, Keitaro, Hayashi, Fumihiko, Kato-Kase, Ikuko, Sunohara, Masataka, Iyoda, Manabu, Koike, Kazuyuki, Nakashima, Dai, Ogawara, Katsunori, Endo-Sakamoto, Yosuke, Shiiba, Masashi, Takiguchi, Yuichi, Yamauchi, Mitsuo, Tanzawa, Hideki
• Format: Article
• Language: English
• Subjects: 38; 38/61; 38/77; 45/23; 631/67/1665; 692/4028/67/1665; 82; 82/51; Animals; Antineoplastic Agents - therapeutic use; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cetuximab - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epidermal growth factor; Epidermal growth factor receptors; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Immunotherapy; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular modelling; Monoclonal antibodies; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; multidisciplinary; Oral cancer; Oral squamous cell carcinoma; Phosphorylation; Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors; Receptors, Urokinase Plasminogen Activator - genetics; Receptors, Urokinase Plasminogen Activator - metabolism; Resveratrol; Resveratrol - pharmacology; Resveratrol - therapeutic use; RNA Interference; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction; Squamous cell carcinoma; Targeted cancer therapy; Transplantation, Heterologous; Tumors; U-Plasminogen activator
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48717-w

Drug resistance to anti-cancer agents is a major concern regarding the successful treatment of malignant tumors. Recent studies have suggested that acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies such as cetuximab are in part caused by genetic alterations in patients with oral squamous cell carcinoma (OSCC). However, the molecular mechanisms employed by other complementary pathways that govern resistance remain unclear. In the current study, we performed gene expression profiling combined with extensive molecular validation to explore alternative mechanisms driving cetuximab-resistance in OSCC cells. Among the genes identified, we discovered that a urokinase-type plasminogen activator receptor (uPAR)/integrin β1/Src/FAK signal circuit converges to regulate ERK1/2 phosphorylation and this pathway drives cetuximab-resistance in the absence of EGFR overexpression or acquired EGFR activating mutations. Notably, the polyphenolic phytoalexin resveratrol, inhibited uPAR expression and consequently the signaling molecules ERK1/2 downstream of EGFR thus revealing additive effects on promoting OSCC cetuximab-sensitivity in vitro and in vivo . The current findings indicate that uPAR expression plays a critical role in acquired cetuximab resistance of OSCC and that combination therapy with resveratrol may provide an attractive means for treating these patients.