Gene interactions and pathways from curated databases and text-mining
J Urol 2013, PMID: 23147251

Inhibition of mTORC2 but not mTORC1 up-regulates E-cadherin expression and inhibits cell motility by blocking HIF-2α expression in human renal cell carcinoma.

Maru, Shintaro; Ishigaki, Yasuhito; Shinohara, Nobuo; Takata, Takanobu; Tomosugi, Naohisa; Nonomura, Katsuya

OBJECTIVE

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.

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.

Diseases/Pathways annotated by Medline MESH: Carcinoma, Renal Cell, Kidney Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

E-cadherin → mTORC2: " We investigated whether mTORC2 regulates E-cadherin expression and controls cell motility during HIF-2a down-regulation in renal cell carcinoma cells "

E-cadherin → mTORC2: " Results show that mTORC2 might regulate E-cadherin expression and suppress cell motility by controlling the mTORC2-HIF-2a signaling pathway "

Manually curated Databases

No curated data.