PURPOSE: Molecular targeted drugs, such as mTORC1 inhibitors, have been clinically popularized for advanced renal cell carcinoma treatment but metastasis is still a serious concern.
mTORC2 has several important functions, including HIF-2α activation in malignant cells. HIF-2α suppresses E-cadherin expression, which is associated with tumor invasion and metastasis. We investigated whether mTORC2 regulates E-cadherin expression and controls cell motility during HIF-2α down-regulation in renal cell carcinoma cells.
MATERIALS AND METHODS: We used PP242, a dual inhibitor of mTORC1/mTORC2 and the mTORC1 specific inhibitor rapamycin. E-cadherin expression in 786-O cells was examined using real-time polymerase chain reaction, Western blot and immunocytochemical staining. Cell motility was analyzed by time-lapse microscopy and wound healing assay.
RESULTS: High E-cadherin expression was found in RCC4/VHL cells but low levels were found in VHL defective RCC4 and 786-O cells. HIF-2α expression was suppressed only in RCC4/VHL cells. In 786-O cells HIF-2α inhibition induced by the dual mTORC1/C2 inhibitor PP242 (0.05 to 0.5 μmol/L) resulted in a dose dependent increase in E-cadherin expression and the restored E-cadherin was localized at cell-to-cell junctions. Treatment with the mTORC1 inhibitor rapamycin resulted in no significant change. The migration of PP242 treated cells was significantly suppressed compared with those treated with rapamycin.
CONCLUSIONS: Results show that mTORC2 might regulate E-cadherin expression and suppress cell motility by controlling the mTORC2-HIF-2α signaling pathway. The dual inhibitor of mTORC1/C2 as a cadherin regulatory agent may be a novel therapeutic strategy with tumoricidal agents for advanced renal cell carcinoma.
Written by:
Maru S, Ishigaki Y, Shinohara N, Takata T, Tomosugi N, Nonomura K. Are you the author?
Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
Reference: J Urol. 2013 May;189(5):1921-9.
doi: 10.1016/j.juro.2012.11.010
PubMed Abstract
PMID: 23147251
UroToday.com Investigative Urology Section
