Influence of Methallothionein Expression on Sensitivity Against Platin Compounds in Human Malignant Pleural Mesothelioma Cell Lines – Knock-Down of Gene Expression as New Therapeutic Approach?

Background Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with dismal prognosis. Platinum-based chemotherapy is often used as part of multimodal therapy. Metallothioneins (MT) are a possible reason for cisplatin resistance, which often leads to early therapy failure or relapse.
Methods The MT gene- and protein-expression of the MPM-cell lines MSTO-211H, NCI-H2052 and NCI-H2452 and the human fibroblast cell line MRC-5, as well as their sensitivity to cisplatin treatment have been evaluated. Knock-down of MT1A, 1B and 2A expression was done by RNA interference. MT expression was measured using quantitative real-time PCR. An in vitro assay based on enzyme activity was used to detect cell viability, necrosis and apoptosis before and after incubation with cisplatin.
Results MT expression levels, especially of MT2A, differs significantly between the analysed cell lines. Additionally, a MT dependent potential of apoptosis induction via cisplatin could be observed, leading to three different MT based cellular phenotypes.
Conclusion Although knock-down of MT2A expression increased the response of the MPM cell lines NCI-H2052 and MSTO-211H to cisplatin treatment, this knock down is not seen as a promising new therapeutic approach as NCI-H2452 does not show a connection between MT expression and cisplatin resistance. In this cell line, another cellular process that does not involve MT has to be the reason for the resistance. In the former two cell lines, MTs are at least a part of the underlying process, which is responsible for the cisplatin resistance. In combination with other biomarkers, MT expression could be used to stratify patients based on the molecular phenotype, saving patients from ineffective, side-effect loaded therapies. This hopefully will gain a benefit for patientsʼ clinical outcome and -management in the near future.