Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis

Abstract

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 lM) or Akt inhibitors (SH-5, 50 lM), whereas inhibition of extracellular-regulated kinase by an ERK inhibitor (PD98059, 10 lM) 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 overexpression 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.

An Orthotopic Model of Metastatic Nasopharyngeal Carcinoma and Its Application in Elucidating a Therapeutic Target That Inhibits Metastasis

“…These are all features that are important in the pathogenesis of primary tumor growth in human NPC disease. 23,24 Focal lymph node invasion was apparent about 20% of the time. By comparison, when we injected C666-1 and HONE-1 cells subcutaneously ( Table 1, experiment 2), we found that the tumors remained encapsulated and contained at the site of injection, showing no signs of invasiveness after 8 weeks of growth (Suppl.…”

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

“…Second, mTORC1 inhibition induces feedback activation of several key mitogenic pathways, including AKT [29,30] and Erk-MAPK [31]. Third, and most importantly, mTORC1 inhibitors showed no direct effect on mTORC2 activation, the latter promoting cell proliferation and migration [16,17,32]. Finally, the bioavailability of rapalogs is often limited [33].…”

“…Second, the mTORC2 substrate AKT (phosphorylation at Ser-473) is known to stimulate cell proliferation and migration [16,17,32]. Third, the cocurrent blockage of mTORC1/2 by OSI-027 was more potent than rapamycin (mTORC1 inhibitor) in inhibiting keloid keratinocytes.…”

“…The complex of mTORC2 primarily consists of mTOR, Rictor, Sin1 and mLST8 [14,15] and functions as an AKT kinase, which phosphorylates AKT at Ser-473 [14,15]. This mTORC2complex is also important for cell proliferation and migration [16,17].…”

Molecular Pathways: P-Rex in Cancer

“…In MCF10A cells that express endogenous active PTEN, forced expression of PRex2a augmented AKT phosphorylation at Ser 473 and favored the formation of multiacinar structures (5), a feature that in these cells has been associated to a pretumorigenic status (27). In ovarian cancer cells, expression of PRex1 has been shown to promote activation of AKT1 and PRex1 knockdown inhibited AKT1 (28).…”