The role of Src kinase in renal cell carcinoma

Renal cancer is a malignancy which is not only increasing in incidence but there has also been an increase in mortality rates. There are various prognostic factors in renal cell cancer. We have demonstrated that some of these such as nuclear grading, tumour necrosis and systemic inflammatory response can be further refined to aid in prognosis but cannot be utilised at present to assess which would benefit from therapeutic agents when recurrence occurs. We investigated if SFK members are expressed in renal cancer. Eight SFK members were found to be expressed in renal cancer and were present to varying degrees. Furthermore, expression differed in organ confined disease and metastatic disease. Immunohistochemistry was employed to assess protein expression and activation of c-Src and SFK activity as well as the downstream marker FAK Y861. Analysis demonstrated that c-Src expression was associated with improved survival and expression of the downstream marker FAK Y861 was associated with poor survival and demonstrated a positive relationship with known prognostic factors. This would suggest that another SFK member was associated with poor survival. Dasatinib, a SFK inhibitor was utilised on renal cell lines, demonstrating a dose dependant reduction on cellular metabolic activity as well an increase in apoptotic rates. This would support that Dasatinib may be a useful therapeutic drug for RCC. Treatment with Dasatinib also demonstrated that expression of c-Src, SFK activity and FAK Y861 reduced in a dose dependant manner. It was necessary to further assess that another SFK member was responsible for poor prognosis and this was undertaken by silencing c-Src. Cellular metabolic activity rates increased following silencing c-Src and assessment of SFK activity (Src Y416) and FAK Y861 on cell pellets demonstrated no change suggesting that another SFK member is responsible for the phosphorylation of FAK Y861 and therefore responsible for poor survival. This would suggest that another SFK inhibitor and not c-Src inhibitors may play a role in the treatment of renal cell cancer and further work is required to ascertain which SFK member is responsible so that this can be targeted for treatment