Integrin α5β1 simultaneously controls EGFR-dependent proliferation and Akt-dependent pro-survival signaling in epidermoid carcinoma cells

Morozevich, G. E.; Kozlova, N. I.; Ушакова, Н. А.; Preobrazhenskaya, M. E.; Berman, A. E.

doi:10.18632/aging.100457

Cited by 46 publications

(46 citation statements)

References 25 publications

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“…In addition to cell proliferation, EGFR signaling impacts other important physiological properties, including migration, differentiation, and apoptosis (21,22). To determine if cell migration was inhibited in response to the cetuximab-induced reduction in EGFR phosphorylation, a wound healing assay in the presence of cetuximab was performed.…”

Section: Cetuximab Inhibits Egfr Phosphorylation Resulting In Reducementioning

confidence: 99%

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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Section: Cetuximab Inhibits Egfr Phosphorylation Resulting In Reducementioning

confidence: 99%

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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“…The link between integrins and growth factor receptors is well known 8,[19][20][21][22][23][24] . Clustering of integrins on cell adhesion concentrates growth factor receptors to sites required for efficient signalling.…”

Section: Resultsmentioning

confidence: 99%

Rb1 family mutation is sufficient for sarcoma initiation

Liu

Sánchez-Tilló

et al. 2013

Nat Commun

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It is thought that genomic instability precipitated by Rb1 pathway loss rapidly triggers additional cancer gene mutations, accounting for rapid tumour onset following Rb1 mutation. However, recent whole-genome sequencing of retinoblastomas demonstrated little genomic instability, but instead suggested rapid epigenetic activation of cancer genes. These results raise the possibility that loss of the Rb1 pathway, which is a hallmark of cancers, might be sufficient for cancer initiation. Yet, mutation of the Rb1 family or inactivation of the Rb1 pathway in primary cells has proven insufficient for tumour initiation. Here we demonstrate that traditional nude mouse assays impose an artificial anoikis and proliferation barrier that prevents Rb1 family mutant fibroblasts from initiating tumours. By circumventing this barrier, we show that primary fibroblasts with only an Rb1 family mutation efficiently form sarcomas in nude mice, and a Ras-ZEB1-Akt pathway then causes transition of these tumours to an invasive phenotype.

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“…Продукцию лентивирусных частиц в клетках HEK293T и инфицирование MCF-7/Dox проводили, как описано ранее [17]. Уровень снижения экспрессии a5-интегрина составлял 70-80% и был примерно одинаковым для двух использованных клонов (данные не приведены).…”

Section: лентивирусные Shrna конструкции и инфицирование клетокunclassified

“…а) клетки инкубировали 24 ч или 48 ч в присутствии PD168393 или 0,5% ДМСО, фиксировали в этаноле, окрашивали иодидом пропидия и анализировали в цитофлуориметре, как описано в в разделе "Методика"; б) клетки инфицировали лентивирусом с плазмидным вектором pLKO.1, содержащим a5-специфическую shRNA, или "пустым" вектором, как описано ранее [17], после чего клетки пассировали в течение указанного времени и обрабатывали для цитофлуориметрии; Ап-апоптотические (суб-G 1 ) клетки; Анэуп -анэуплоидные клетки; цифры представляют относительное содержание (%) каждой популяции. Представлены результаты типичного опыта.…”

Section: рисунокunclassified

“…Представленные результаты согласуются с данными наших исследований, проведённых на линии A431 эпидермоидной карциномы человека, которые показали, что блокирование экспрессии интегрина a5b1 и торможение активности EGFR в клетках А431 оказывают очень близкий по динамике и интенсивности ингибирующий эффект на их пролиферацию [17]. Отличие между исследованными линиями заключалось в том, что в клетках A431 ингибирование EGFR приводило к задержке цикла в фазе G 0 /G 1 , тогда как в клетках MCF-7/Dox торможение наблюдалось в S фазе.…”

Section: рисунокunclassified

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Implication of integrin alpha5beta1 signal pathways in proliferation and apoptosis of MCF-7/Dox human breast carcinoma cells

et al. 2016

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In MCF-7/Dox human breast carcinoma cells, down-regulation of integrin alpha5beta1 and inhibition of epidermal growth factor receptor (EGFR) markedly reduced rates of cell proliferation. Mitotic cycle analysis showed that alpha5beta1 down-regulation resulted in cell cycle arrest at the S phase, followed by a significant increase in the population of apoptotic cells (subG1 population). Inhibition of EGFR activity also caused cell cycle arrest at the S-phase but without any increase in the subG1 population. Down-regulation of alpha5beta1 and EGFR inhibition resulted in a significant decrease of cell content of the active (phosphorylated) forms of FAK and Erk protein kinases. The data obtained suggest that alpha5beta1 integrin is implicated in cell growth control via inhibition of apoptotic cell death and through EGFR activation.

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Integrin α5β1 simultaneously controls EGFR-dependent proliferation and Akt-dependent pro-survival signaling in epidermoid carcinoma cells

Cited by 46 publications

References 25 publications

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

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

Rb1 family mutation is sufficient for sarcoma initiation

Implication of integrin alpha5beta1 signal pathways in proliferation and apoptosis of MCF-7/Dox human breast carcinoma cells

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