Potential therapy with the inhibitor of TGF-β receptors LY2109761 for oral squamous cell carcinoma

Arthur Silva Rezende,Anna Cecília Dias Maciel Carneiro,Bruna Raphaela Oliveira Silva,Simone De Sales Costa Moreira Carboni,Virginia Oliveira Crema

doi:10.33448/rsd-v10i9.18396

Arthur Silva Rezende, Anna Cecília Dias Maciel Carneiro + Show 3 more

Open Access

https://doi.org/10.33448/rsd-v10i9.18396

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Abstract

One way of trying to control oral squamous cell carcinoma is to invest in new therapies focused on the molecular biology of receptors and their intracellular signaling pathways. This study aimed to evaluate the effect of LY2109761 (an inhibitor of TGF-β receptors) on cell migration in oral squamous cell carcinoma in vitro. Actin cytoskeleton of SCC-4 cells control and LY2109761 (1, 5 and 10 μM) treated on three-dimensional Matrigel were analysed by using confocal laser microscopy. Control and LY2109761 (1, 5 and 10 μM) treated cells that migrated through the membrane of three-dimensional cell migration assays were counted, significance was p<0.05. Control cells were seen with voluminous cytoplasm, cell cortex preserved and actin cytoskeleton well developed with well distributed actin filaments. Regardless of concentration, cells treated showed: rounded morphology and small size, scanty cytoplasm, cortical F-actin less clear that the control cells, and disruption of actin filaments. The migratory cells were inhibited by treatment with LY2109761 [F (3, 11) = 3742, p<0.0001], in a dose-dependent manner. These results suggest that LY2109761 exerts an inhibitory effect on the actin cytoskeleton and cell migration on SCC-4 cells, therefore, it is a promising therapeutic option for oral squamous cell carcinoma.

Highlights

Among head and neck tumors, oral squamous cell carcinomas account for 90% of cases, whose primary lesions may present as symptoms like difficulty in swallowing and hoarseness, and the prognosis for early cases is promising, unlike advanced cases, where regional and/or distance metastasis are common (Sanderson & Ironside, 2002)
This study aimed to evaluate the effect of LY2109761 treatment, by using three-dimensional assays, on the regulation of the actin cytoskeleton and cell migration in oral squamous cell carcinoma in vitro
Control cells were seen with morphology: polarized, voluminous cytoplasm, eccentric spherical nuclei, cell cortex preserved and actin cytoskeleton well developed with well distributed actin filaments

Summary

Introduction

Among head and neck tumors, oral squamous cell carcinomas account for 90% of cases, whose primary lesions may present as symptoms like difficulty in swallowing and hoarseness, and the prognosis for early cases is promising, unlike advanced cases, where regional and/or distance metastasis are common (Sanderson & Ironside, 2002). During the development of metastasis, the displacement of cells within primary site tissues, cell migration, occurs to target distant organs at secondary sites (Krakhmal et al, 2015); (Albini & Noonan, 2010; Kramer et al, 2013), when cell migration occurs (Albini & Noonan, 2010). It is important the development of new therapeutics (Capece et al, 2017), the blockade of the TGF-β signaling pathway is a promising therapeutic option (Neuzillet et al, 2015). The LY2109761 is a dihydropyrrolopyrazole inhibitor which has oral bioactivity and a potential of inhibition in vivo greater than 50% (Li et al, 2008) and acts on the intracellular domain of the TGF-β type I receptor (TβRI), through competition for the catalytic site of ATP blocking phosphorylation of the receptor and activation of the intracellular signaling pathway (Connolly et al, 2012)

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