Abstract
Background: The importance of caspase-2 activation for mediating apoptosis in cancer is not clear and seems to differ between different tumour types. Furthermore, only few data have been obtained concerning the expression of caspase-2, which can be alternatively spliced into caspase-2L and caspase-2S, and the other PIDDosome members PIDD and RAIDD in human tumours in vivo. We, therefore, investigated their expression in renal cell carcinomas (RCCs) of the clear cell type in vivo and analysed the role of caspase-2 in chemotherapy-induced apoptosis in RCCs in vitro.Methods: The analyses were performed by semiquantitative real-time PCR, Western Blot and Caspase-2 Assay.Results: Our in vivo results showed an overall decrease in proapoptotic caspase-2L expression during tumour progression due to an increase in the relative share of caspase-2S mRNA in total caspase-2 mRNA expression. Furthermore, an increase in the expression of PIDD and RAIDD could be observed. In contrast, antiapoptotic BCL-2 expression increased only during early tumour stages, whereas expression decreased in pT3 RCCs. In vitro, caspase-2 activation in RCC cell lines coincidenced with sensitivity of tumour cells towards Topotecan-induced apoptosis. However, inhibition of caspase-2 could not prevent Topotecan-induced apoptosis. Interestingly, Topotecan-resistance could be overcome by the apoptosis-sensitizing drug HA14-1.Conclusions: Our study confirms the concept of a shift towards a more antiapoptotic transcriptional context during tumour progression in RCCs. Furthermore, it shows that caspase-2 participates in chemotherapy-induced apoptosis in RCCs although it is not mandatory for it. Additionally, inhibition of antiapoptotic BCL-2 family members might provide a possible way to overcome chemotherapy resistance of RCCs.
Highlights
The broad resistance of renal cell carcinomas (RCCs) towards chemo- and radiotherapy is a major difficulty in treatment of advanced tumour stages [1,2]
The aim of our study was to analyse expression of the PIDDosome components caspase-2, PIDD and RAIDD and of the important caspase-2 inhibiting factors caspase-2S as well as BCL-2 in RCCs in vivo to determine their meaning for tumour progression
Total caspase-2 and caspase-2S are upregulated during tumour progression in RCCs whereas caspase-2L is downregulated mRNA expression of total caspase-2 and caspase-2S was found in all RCCs and in all corresponding nonneoplastic renal tissues
Summary
The broad resistance of renal cell carcinomas (RCCs) towards chemo- and radiotherapy is a major difficulty in treatment of advanced tumour stages [1,2] Until recently, these patients had few treatment options beyond cytokine therapy (interleukin-2 and interferonα (IFN-α)), but new targeted therapies with Sunitinib, Bevacizumab and Temsirolimus in combination with IFN-α lately revealed improved progression free survival and response rates compared to INF-α alone. Only few data have been obtained concerning the expression of caspase-2, which can be alternatively spliced into caspase-2L and caspase-2S, and the other PIDDosome members PIDD and RAIDD in human tumours in vivo We, investigated their expression in renal cell carcinomas (RCCs) of the clear cell type in vivo and analysed the role of caspase-2 in chemotherapy-induced apoptosis in RCCs in vitro
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