Ras-transfected human mammary tumour cells are resistant to photodynamic therapy by mechanisms related to cell adhesion

Abstract

Aims: Photodynamic therapy (PDT) is a treatment modality for several cancers involving the administration of a tumour-localising photosensitiser (PS) and its subsequent activation by light, resulting in tumour damage. Ras oncogenes have been strongly associated with chemo- and radio-resistance. Based on the described roles of adhesion and cell morphology on drug resistance, we studied if the differences in shape, cell-extracellular matrix and cell-cell adhesion induced by Ras transfection, play a role in the resistance to PDT. Materials and methods: We employed the human normal breast HB4a cells transfected with H-RAS and a panel of five PSs. Key findings: We found that resistance to PDT of the HB4a-Ras cells employing all the PSs, increased between 1.3 and 2.5-fold as compared to the parental cells. There was no correlation between resistance and intracellular PS levels or PS intracellular localisation. Even when Ras-transfected cells present lower adherence to the ECM proteins, this does not make them more sensitive to PDT or chemotherapy. On the contrary, a marked gain of resistance to PDT was observed in floating cells as compared to adhesive cells, accounting for the higher ability conferred by Ras to survive in conditions of decreased cell-extracellular matrix interactions. HB4a-Ras cells displayed disorganisation of actin fibres, mislocalised E-cadherin and vinculin and lower expression of E-cadherin and β1-integrin as compared to HB4a cells. Significance: Knowledge of the mechanisms of resistance to photodamage in Ras-overexpressing cells may lead to the optimization of the combination of PDT with other treatments.