Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

Ohnishi, Yozo; Minamino, Yuki; Kakudo, Kenji; Nozaki, Masami

doi:10.3892/or.2014.3258

Cited by 19 publications

(24 citation statements)

References 39 publications

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“…The proliferation of SAS cells, which possess a stem cell-like potency (52), was resistant to cetuximab in monolayer culture conditions, despite the phosphorylation of EGFR; however, the growth of SAS cell aggregates, in which EGFR levels were increased, was sensitive to cetuximab (30). In the present study, it was demonstrated that SAS cell migration is also sensitive to the EGFR inhibitors cetuximab and AG1478.…”

Section: Discussionmentioning

confidence: 56%

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

et al. 2016

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Abstract. Cell migration potency is essential in cancer metastasis and is often regulated by extracellular stimuli. Oral squamous cell carcinoma cell lines include those that are sensitive, as well as resistant, to the effects of the epidermal growth factor receptor (EGFR) inhibitor cetuximab on cell migration. In the present study, the molecular differences in the EGFR response to cell migration between the SAS cetuximab-sensitive and HSC4 cetuximab-resistant cell lines was examined. Treatment with the EGFR inhibitors AG1478 and cetuximab reduced the migration potency of SAS cells, but not HSC4 cells. The migration of the two cell lines was inhibited under serum-free culture conditions, and the addition of EGF to the serum-free medium promoted the migration of SAS cells, but not HSC4 cells. In addition, SAS cell migration was reduced by the mitogen-activated protein kinase kinase and protein kinase B (Akt) inhibitors PD98059 and MK2206, whereas HSC4 cell migration was only inhibited by MK2206. EGF induced an increase in extracellular signal-regulated kinase phosphorylation levels in HSC4 cells, and stimulated Akt phosphorylation levels in SAS cells. Furthermore, the staining of actin filaments with phalloidin was significantly increased by the inhibition of EGFR in SAS cells, but was not observed as altered in HSC4 cells. Conversely, the addition of EGF to the culture medium decreased the accumulation of actin filaments in SAS cells. The results suggest that the EGF-EGFR signaling pathway has an important role in SAS cell migration via the modulation of actin dynamics, and that HSC4 cell migration is regulated by a serum component other than EGFR.

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Section: Discussionmentioning

confidence: 56%

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

et al. 2016

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“…Furthermore, EGFR phosphorylation levels were increased by serum stimulation (Fig. 1B), although SAS cells actively proliferate in serum-free culture conditions as described previously (19). These results indicate that the inhibitory effects of cetuximab on EGFR phosphorylation are weaker than those of AG1478, and EGFR phosphorylation signals are not the main factor inducing proliferation of SAS cells in monolayer cultures.…”

Section: Cetuximab Inhibits Egfr Phosphorylation Resulting In Reducementioning

confidence: 47%

“…We previously reported that SAS cell growth is poorly sensitive to cetuximab or AG1478 treatment in a monolayer culture, even though EGFR is expressed and phosphorylated (19), indicating that EGFR phosphorylation is minimally involved in SAS cell proliferation.…”

Section: Cetuximab Inhibits Egfr Phosphorylation Resulting In Reducementioning

confidence: 99%

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Cetuximab-resistant oral squamous cell carcinoma cells become sensitive in anchorage-independent culture conditions through the activation of the EGFR/AKT pathway

Ohnishi

Yasui

Kakudo

et al. 2015

International Journal of Oncology

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Abstract.We have previously shown that growth of the oral squamous cell carcinoma cell line SAS, is resistant to cetuximab in monolayer culture conditions, even though epidermal growth factor receptor (EGFR) was phosphorylated, but the growth of SAS aggregates was sensitive to cetuximab. In the present study, we demonstrate differences in the EGFR signaling pathways utilized by SAS cells in monolayer and suspension cultures at the molecular level. Cetuximab treatment of SAS cells in monolayer cultures inhibits the phosphorylation of EGFR and ERK, and reduces the cell migratory potency, but not cell proliferation. AG1478 treatment reduces the phosphorylation of EGFR, ERK and AKT, and affects cell growth in monolayer cultures. The phosphorylation levels of EGFR and AKT are significantly higher in SAS cell aggregates compared to monolayer cultures. Treatment with cetuximab and AG1478 reduces the growth of SAS aggregates and eliminates the phosphorylation of EGFR and AKT. Furthermore, proliferation of SAS aggregates is also inhibited by LY294002 and MK2206, which are inhibitors of PI3K and AKT, respectively. In addition, treatment with the lipid raft disruptor filipin III reduced the phosphorylation levels of EGFR and Akt in SAS aggregates, but not in SAS monolayer culture. These results suggest the possibility that ligands in the serum stimulate the phosphorylation of EGFR localized in lipid rafts leading to PI3K-AKT activation, which results in the growth of SAS aggregates, therefore resulting in the sensitivity of SAS aggregates to cetuximab. IntroductionHead-and-neck squamous cell carcinoma (HNSCC) is the most common cancer in the head and neck region, and affects ~550,000 patients worldwide (1). The overall 5-year survival rate of HNSCC including oral squamous cell carcinoma (OSCC) is ~50%, which has not improved markedly during the last decade (2,3). Thus, new effective therapeutic modalities are needed to improve survival of HNSCC patients.The epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinase (TK) or HER family, which consists of EGFR (HER1/ErbB1), HER2/Neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Stimulation of the receptors through ligand binding activates the receptor tyrosine kinase and promotes its homodimerization or heterodimerization with another HER. EGFR activation stimulates a number of downstream signaling cascades, such as the RAS/RAF/ERK/ MAPK, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, and the phospholipase C-γ/protein kinase C (PLCγ/PKC) pathway, and including the Src family kinases (SFKs), and the signal transducers and activators of transcription (STATs). These pathways affect various cellular responses, including proliferation, survival, migration, angiogenesis and metastasis (4-10).EGFR is constitutively distributed in normal epithelial cells, but it is highly expressed in various cancers, including those of the breast, prostate, and lung cancers, as well as gliomas (11). EGFR is expressed at higher levels in >95% of HNSCCs compared to normal mucosa...

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“…EGFR-targeted therapies, including gefitinib (Iressa ® ; AstraZeneca, London, UK) (26,(28)(29)(30) and cetuximab (Erbitux ® ; Eli Lilly and Company, Indianapolis, IN, USA) (31,32), have been studied extensively as potential methods of blocking the cancer-promoting functions of EGFR in OSCC. However, although it has been reported that EGFR inhibitors are initially beneficial for the treatment of cancer, resistance to the inhibitors eventually develops (21,33). Therefore, an alternative strategy was investigated in the present study, in which rather than targeting the EGFR protein, the expression of its gene, EGFR, in OSCC was downregulated using RNAi techniques.…”

Section: Discussionmentioning

confidence: 99%

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2

Chen

Lovel

et al. 2016

Oncology Letters

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Abstract. Oral cancer is the eighth most common type of cancer among men worldwide, with an age-standardized rate of 6.3 per 100,000, and is the fourth leading cause of cancer-associated mortality among men in Taiwan. Cisplatin and 5-fluorouracil (5-FU) are two of the most frequently utilized chemotherapy drugs for the treatment of oral cancer. Although oral cancer patients initially benefit from chemotherapy with these drugs, they may develop resistance to them, which worsens their prognosis and reduces survival rates. It has been reported that increased levels of epidermal growth factor receptor (EGFR) and multidrug resistance-associated protein 2 (MRP2) induce drug resistance in numerous types of human cancer. Therefore, the present study employed lentivirus vector-mediated RNA interference (RNAi) in order to target the genes encoding EGFR and MRP2 in the oral squamous cell carcinoma cell line OC2. It was observed that RNAi-mediated downregulation of EGFR or MRP2 increased the sensitivity to 5-FU and cisplatin in OC2 cells. Downregulation of EGFR resulted in significant suppression of OC2 tumor growth following 5-FU administration. However, simultaneous downregulation of the two genes did not further suppress the tumor growth, indicating that MRP2 does not have a significant role in the chemosensitivity of EGFR-downregulated cells to 5-FU. In contrast, downregulation of MRP2 was demonstrated to significantly enhance the therapeutic effects of cisplatin in EGFR-downregulated OC2 tumors. The observation that the expression of MRP2 was positively correlated with the level of cisplatin resistance in cells suggests that RNAi-mediated downregulation of MRP2 may be applicable as a therapeutic approach toward reversing MRP2-dependent cisplatin resistance in oral cancer. IntroductionOral cancer is the eighth most common type of cancer among men worldwide, with an age-standardized rate of 6.3 per 100,000 (1,2), and is the fourth leading cause of cancer-associated mortality among men in Taiwan (3). In addition, oral cancer has been ranked highest with respect to the rates of incidence and mortality among men aged 25-44 years in Taiwan since 2005 (3). Chemotherapy has been used as the primary treatment for patients exhibiting recurrent or metastatic cancers, including oral cancer (4). Of the various chemotherapy drugs available, cisplatin and 5-fluorouracil (5-FU) are the two most frequently utilized for the treatment of oral cancer (5). However, the efficacy of cancer chemotherapy is often limited by the development of drug resistance by the cancer cells in clinical practice (6).It has been demonstrated that multidrug resistance results largely from the expression of adenosine triphosphate-binding cassette (ABC) transporters with broad drug specificity (7-9). Multidrug resistance-associated protein 2 (MRP2), a member of the ABC transporter superfamily, has been observed in various tumors to confer resistance to a number of therapeutic drugs, including cisplatin (10-12). The levels of MRP2 messenger (m)RNA in certain hum...

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Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

Cited by 19 publications

References 39 publications

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

Cetuximab-resistant oral squamous cell carcinoma cells become sensitive in anchorage-independent culture conditions through the activation of the EGFR/AKT pathway

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2

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