mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis

Cancer Res. 2010 Nov 15;70(22):9360-70. doi: 10.1158/0008-5472.CAN-10-0207. Epub 2010 Oct 26.

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 RNA-mediated 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chemotaxis / drug effects
  • Epidermal Growth Factor / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, SCID
  • Microscopy, Confocal
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • RNA Interference
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Heterologous

Substances

  • Carrier Proteins
  • RICTOR protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Epidermal Growth Factor
  • protein kinase C zeta
  • Protein Kinase C