Rodriguez Lorena, Di Venosa Gabriela, Rivas Martín A, Juarranz Angeles, Sanz-Rodriguez Francisco, Casas Adriana
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), Universidad de Buenos Aires, Hospital de Clínicas José de San Martín and CONICET, Ciudad de Buenos Aires, Argentina.
Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Life Sci. 2023 Feb 1;314:121287. doi: 10.1016/j.lfs.2022.121287. Epub 2022 Dec 14.
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.
We employed the human normal breast HB4a cells transfected with H-RAS and a panel of five PSs.
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.
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.
光动力疗法（PDT）是一种用于多种癌症的治疗方式，涉及给予肿瘤定位光敏剂（PS）并随后用光激活，从而导致肿瘤损伤。Ras癌基因与化疗和放疗耐药性密切相关。基于所描述的黏附及细胞形态对耐药性的作用，我们研究了Ras转染诱导的细胞形状、细胞 - 细胞外基质及细胞 - 细胞黏附差异是否在对PDT的耐药性中起作用。
我们使用了转染了H - RAS的人正常乳腺HB4a细胞及一组五种PS。
我们发现，与亲代细胞相比，使用所有PS的HB4a - Ras细胞对PDT的耐药性增加了1.3至2.5倍。耐药性与细胞内PS水平或PS细胞内定位之间无相关性。即使Ras转染细胞对细胞外基质蛋白的黏附性较低，但这并未使它们对PDT或化疗更敏感。相反，与贴壁细胞相比，在悬浮细胞中观察到对PDT的耐药性显著增加，这解释了Ras赋予细胞在细胞 - 细胞外基质相互作用减少的条件下更高的存活能力。与HB4a细胞相比，HB4a - Ras细胞显示肌动蛋白纤维紊乱、E - 钙黏蛋白和纽蛋白定位错误以及E - 钙黏蛋白和β1 - 整合素表达降低。
了解Ras过表达细胞对光损伤的耐药机制可能会导致PDT与其他治疗方法联合使用的优化。
