Ildikó Krencz1, Anna Sebestyén1, Gyula Végső2, Enikő Vetlényi1, Dorottya Moldvai1, Titanilla Dankó1, Gábor Petővári1, Zoltán Hujber1, Judit Pápay1
1 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
2 Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
Introduction: Tacrolimus is a calcineurin inhibitor (CNI) widely used in kidney transplantation. It can reduce the risk of allograft rejection; however, prolonged treatment leads to progressive nephrotoxicity and the development of post-transplant malignancies.
Aims: The aim of our study was to analyze the effect of the CNI and mTOR inhibitor treatment on the proliferation and mTOR pathway activation in renal cell carcinoma (RCC) in vitro and in vivo.
Method: The effect of tacrolimus and mTOR inhibitors on the proliferation and mTOR pathway activation was analyzed in renal cell carcinoma and “normal” tubular epithelial cell lines. The expression of p-mTOR, p-S6, Rictor and PTEN was assessed by immunohistochemistry in post-transplant RCCs as compared to non-transplant RCCs, end-stage renal disease (ESRD), and normal kidney.
Results: In tubular epithelial cells, tacrolimus treatment had no significant effect on proliferation, however, resulted in an increase of mTOR activity. Similarly, mTOR activity appeared to be higher in end-stage kidneys of transplant recipients compared to ESRD patients who have not received CNI as immunosuppressive therapy. The mTORC2 activity was significantly higher in post-transplant than in non-transplant RCCs, especially in papillary RCCs. Moreover, PTEN expression was moderately decreased in post-transplant papillary RCCs. Tacrolimus treatment promoted the proliferation of two of the three RCC cell lines and long-term treatment resulted in an increase of mTORC1/2 activity, as well. In our in vitro studies, the mTORC1/2 inhibitor PP242 showed a higher antiproliferative effect in all RCC cell lines as compared to rapamycin.
Conclusion: Our results underline the role of the CNI treatment in the activation of the mTOR pathway which may contribute to the development of post-transplant RCCs. Conversion from CNI to mTOR-inhibitor-based immunosuppression may have a potential benefit to prevent or treat post-transplant malignancies.
This work was supported by the ÚNKP-18-3 New National Excellence Program of The Ministry of Human Capacities (I. K.), FKIP Higher Education Excellence Program at Semmelweis University (A. S.), NKFI-FK-128404 National Research, Development and Innovation Office (A. S.), EFOP-3.6.3-VEKOP-16-2017-00009 (G. P.), and National Bionics Program of Hungary.
Doctoral School: Doctoral School of Pathological Sciences
Supervisor: Judit Pápay, MD, PhD
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