Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis.
Mammalian target of rapamycin complex (mTORC) regulates a variety of cellular responses including proliferation, growth, differentiation and cell migration. In this study, we show that mammalian target of rapamycin complex 2 (mTORC2) regulates invasive cancer cell migration through selective activation of Akt1. Insulin-like growth factor-1 (IGF-1)-induced SKOV-3 cell migration was ... completely abolished by phosphatidylinositol 3-kinase (PI3K) (LY294002, 10 μM) or Akt inhibitors (SH-5, 50 μM), whereas inhibition of extracellular-regulated kinase by an ERK inhibitor (PD98059, 10 μM) or inhibition of mammalian target of rapamycin complex 1 (mTORC1) by an mTORC1 inhibitor (Rapamycin, 100 nM) did not affect IGF-1-induced SKOV-3 cell migration. Inactivation of mTORC2 by silencing Rapamycin-insensitive companion of mTOR (Rictor), abolished IGF-1-induced SKOV-3 cell migration as well as activation of Akt. However, inactivation of mTORC1 by silencing of Raptor had no effect. Silencing of Akt1 but not Akt2 attenuated IGF-1-induced SKOV-3 cell migration. Rictor was preferentially associated with Akt1 rather than Akt2, and over-expression of Rictor facilitated IGF-1-induced Akt1 activation. Expression of PIP3-dependent Rac exchanger1 (P-Rex1), a Rac guanosine exchange factor and a component of the mTOR complex, strongly stimulated activation of Akt1. Furthermore, knockdown of P-Rex1 attenuated Akt activation as well as IGF-1-induced SKOV-3 cell migration. Silencing of Akt1 or P-Rex1 abolished IGF-1-induced SKOV-3 cell invasion. Finally, silencing of Akt1 blocked in vivo metastasis, whereas silencing of Akt2 did not. Given these results, we suggest that selective activation of Akt1 through mTORC2 and P-Rex1 regulates cancer cell migration, invasion and metastasis.
Mesh Terms:
Cell Movement, Cells, Cultured, Enzyme Activation, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors, Humans, Insulin-Like Growth Factor I, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Substrate Specificity, Transcription Factors, rac1 GTP-Binding Protein
Cell Movement, Cells, Cultured, Enzyme Activation, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors, Humans, Insulin-Like Growth Factor I, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Substrate Specificity, Transcription Factors, rac1 GTP-Binding Protein
Oncogene
Date: Jun. 30, 2011
PubMed ID: 21339740
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