microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKK beta-mTORC1 axis to regulate renal cancer cell invasion

作者：Bera Amit; Das Falguni; Ghosh Choudhury Nandini; Kasinath Balakuntalam S; Abboud Hanna E; Choudhury Goutam Ghosh^*

来源：Experimental Cell Research, 2014, 328(1): 99-117.

DOI：10.1016/j.yexcr.2014.06.022

• Renal carcinoma
• miR-21
• Akt kinase
• mTOR

Renal cancer metastasis may result from oncogenic forces that contribute to the primary tumor. We have recently identified microRNA-21 as an oncogenic driver of renal cancer cells. The mechanism by which miR-21 controls renal cancer cell invasion is poorly understood. We show that miR-21 directly downregulates the proapoptotic protein PDCD4 to increase migration and invasion of ACHN and 786-O renal cancer cells as a result of phosphorylation/activation of Akt and IKK beta, which activate NF kappa B-dependent transcription. Constitutively active (CA) Akt or CA IKK beta blocks PDCD4-mediated inhibition and restores renal cancer cell migration and invasion. PDCD4 inhibits mTORC1 activity, which was reversed by CA IKK beta. Moreover, CA mTORC1 restores cell migration and invasion inhibited by PDCD4 and dominant negative IKK beta. Moreover, PDCD4 negatively regulates mTORC2-dependent Akt phosphorylation upstream of this cascade. We show that PDCD4 forms a complex with rictor, an exclusive component of mTORC2, and that this complex formation is reduced in renal cancer cells due to increased miR-21 expression resulting in enhanced phospholylation of Akt. Thus our results identify a previously unrecognized signaling node where high miR-21 levels reduce rictor PDCD4 interaction to increase phosphorylation of Akt and contribute to metastatic fitness of renal cancer cells.

• 出版日期2014-10-15