Ildikó Krencz1, Gyula Végső2, Anna Sebestyén1, Titanilla Dankó1, Gábor Petővári1, Zoltán Hujber1, Judit Pápay1
1 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest
2 Department of Transplantation and Surgery, Semmelweis University, Budapest
Introduction: The PI3K/Akt/mTOR pathway has a fundamental role in renal physiology and its inhibitors are used as immunosuppressive as well as anti-tumour agents. Recent studies suggest that immunosuppressive treatment may influence mTOR pathway activation.
Aims: The aim of our study was to analyse the role of mTORC1/C2 activity in post-transplant renal cell carcinoma (RCC).
Method: Protein expression of p-mTOR (catalytic subunit of mTORC1 and mTORC2), p-S6 (mTORC1-related protein) and Rictor (mTORC2-related protein) was assessed by immunohistochemistry in post-transplant (n=46) and non-transplant (n=46) RCCs. Tissues from patients with end-stage renal disease (ESRD) (n=10) and normal kidney (n=3) were also studied. RCC (786-O, A498) and normal proximal tubular cell lines (HK-2, NRK) were treated with tacrolimus (calcineurin inhibitor), rapamycin (mTORC1 inhibitor), and PP242 (mTORC1/C2 inhibitor) and Alamar Blue proliferation assay was performed.
Results: Expression of p-S6 and p-mTOR was weak and expression of Rictor was high in normal tubular epithelial cells. In ESRD, expression of p-mTOR, p-S6, and Rictor appeared to be higher in transplant recipients compared to those who have not received immunosuppression. Expression of p-mTOR and Rictor was significantly higher in RCCs of diseased native kidneys of renal transplant recipients compared to RCCs developed in healthy individuals (P<0.01). Rapamycin inhibited the proliferation of NRK, HK-2 and 786-O cells (P<0.05), however, A498 was rapamycin-resistant. PP242 suppressed proliferation more effectively in all cell lines (P<0.001). Tacrolimus did not affect proliferation at immunosuppressive dose, however, higher concentration promoted proliferation of A498 cells (P<0.05).
Conclusion: There are few evidences for the protective role of mTOR inhibitors as immunosuppressive agents against post-transplant renal malignancies. Our results highlighted the role of mTORC2 in the pathobiology of post-transplant RCCs. Based on our results, using dual mTORC1/C2 inhibitors as immunosuppressive and/or anti-tumour treatment may represent a promising opportunity to prevent and cure post-transplant RCCs.
Supported by the ÚNKP-17-3 New National Excellence Program of the Ministry of Human Capacities, scientific grant of the Hungarian Respiratory Foundation, Bolyai Found of Hungarian Academy Sciences, and Semmelweis University Innovation Found STIA-KF-17.
Doctoral School: Doctoral School of Pathological Sciences
Supervisor: Judit Pápay
E-mail address: email@example.com