mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis.
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.
Zhang
Fei
F
Tianjin Medical University, Cancer Institute and Hospital, Research Center of Basic Medical Sciences, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin, China.
Zhang
Xiaofang
X
Li
Menghui
M
Chen
Peng
P
Zhang
Bin
B
Guo
Hua
H
Cao
Wenfeng
W
Wei
Xiying
X
Cao
Xuchen
X
Hao
Xishan
X
Zhang
Ning
N
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D000099221:Protein Kinase C zeta
D002352:Carrier Proteins; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000099221:Protein Kinase C zeta; C492571:RICTOR protein, human