mTOR Complex Component Rictor Interacts with PKCζ and Regulates Cancer Cell Metastasis

Abstract

Epidermal growth factor (EGF) mediates breast cancer cell chemotaxis and metastasis through mechanisms that involve the growth-regulatory mammalian target of rapamycin (mTOR) complex mTORC2, but the mechanisms involved remain obscure. Here, we report that the rapamycin-insensitive mTORC2 component protein Rictor is a critical mediator of metastasis in breast cancer cells. In patients with ductal carcinoma, Rictor expression was associated with increased lymph node metastasis. EGF induced translocation and colocalization of Rictor with protein kinase Cζ (PKCζ), a pivotal molecule in chemotaxis signaling. Further, Rictor coimmunoprecipitated with PKCζ in the absence of the mTORC2 complex. Small interfering RNAmediated knockdown of Rictor inhibited EGF-induced PKCζ phosphorylation and translocation along with phosphorylation of the key F-actin binding protein cofilin. In parallel, Rictor knockdown reduced cellular chemotactic capacity and ablated pulmonary metastasis in a xenograft mouse model of breast cancer. Our findings identify Rictor as an important mediator of chemotaxis and metastasis in breast cancer cells.

Next-generation sequencing reveals lymph node metastasis associated genetic markers in colorectal cancer

“…In tumor cells, EGF may mediate proliferation by activating the EGF receptor pathway which leads to tumor cells survival and metastasis (18). Previous studies demonstrated that EGF is able to induce tumor metastasis through matrix metalloproteinases (19), tyrosine kinase PK2 (20), Podoplanin (21), Rictor binding protein (22), epithelial mesenchymal transition (23) and improving blood vessel (24) and lymph gland growth (25,26). In the present study, the mRNA level of EGF was significantly upregulated in patients with lymph node metastasis, which indicated that EGF may be associated with lymph node metastasis in colorectal cancer.…”

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

“…30. A375 and MUM‐2B cells pre‐treated with scrambled control oligomer (scr) or shRictor were cultured in 6‐well culture plates in a monolayer at 80–90% confluence.…”

mTOR complex 2 signaling and functions

“…Rictor was found to interact with PKCζ and mediates chemotaxis and metastasis in breast cancer cells. 94 However, this rictor function appears to be mTORC2-independent and could occur when rictor expression becomes elevated. In colorectal cancer cells, both mTORC2 and mTORC1 could regulate cell motility and metastasis via the Rho GTPases.…”