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mTORC2 Activity Is Elevated in Gliomas and Promotes Growth and Cell Motility via Overexpression of Rictor

¹ Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda, California and ² Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California

Requests for reprints: Joseph Gera, Research and Development (151), Greater Los Angeles VA Healthcare System, 16111 Plummer Street, Building 1, Room C111A, Sepulveda, CA 91343-2099. Phone: 818-895-9416; Fax: 818-895-9554; E-mail: gera{at}ucla.edu.

mTORC2 is a multimeric kinase composed of the mammalian target of rapamycin kinase (mTOR), mLST8, mSin1, and rictor. The complex is insensitive to acute rapamycin exposure and has shown functions in controlling cell growth and actin cytoskeletal assembly. mTORC2 has recently been shown to phosphorylate and activate Akt. Because 70% of gliomas harbor high levels of activated Akt, we investigated whether mTORC2 activity was elevated in gliomas. In this study, we found that mTORC2 activity was elevated in glioma cell lines as well as in primary tumor cells as compared with normal brain tissue (P < 0.05). Moreover, we found that rictor protein and mRNA levels were also elevated and correlated with increased mTORC2 activity. Overexpression of rictor in cell lines led to increased mTORC2 assembly and activity. These lines exhibited increased anchorage-independent growth in soft agar, increased S-phase cell cycle distribution, increased motility, and elevated integrin β₁ and β₃ expression. In contrast, small interfering RNA–mediated knockdown of rictor inhibited these oncogenic activities. Protein kinase C (PKC) activity was shown to be elevated in rictor-overexpressing lines but reduced in rictor-knockdown clones, consistent with the known regulation of actin organization by mTORC2 via PKC. Xenograft studies using these cell lines also supported a role for increased mTORC2 activity in tumorigenesis and enhanced tumor growth. In summary, these data suggest that mTORC2 is hyperactivated in gliomas and functions in promoting tumor cell proliferation and invasive potential due to increased complex formation as a result of the overexpression of rictor. [Cancer Res 2007;67(24):11712–20]

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