Abstract
mTOR complex 2 (mTORC2) signaling is upregulated in multiple types of human cancer, but the molecular mechanisms underlying its activation and regulation remain elusive. Here, we show that microRNA-mediated upregulation of Rictor, an mTORC2-specific component, contributes to tumor progression. Rictor is upregulated via the repression of the miR-424/503 cluster in human prostate and colon cancer cell lines that harbor c-Src upregulation and in Src-transformed cells. The tumorigenicity and invasive activity of these cells were suppressed by re-expression of miR-424/503. Rictor upregulation promotes formation of mTORC2 and induces activation of mTORC2, resulting in promotion of tumor growth and invasion. Furthermore, downregulation of miR-424/503 is associated with Rictor upregulation in colon cancer tissues. These findings suggest that the miR-424/503–Rictor pathway plays a crucial role in tumor progression.
Highlights
The evolutionarily conserved Ser/Thr kinase mTOR plays pivotal roles in regulating cell growth, proliferation, and survival [1,2]
Dysregulation of mTOR signaling is frequently observed in many types of cancers, implicating it in promotion of tumor growth and malignancy [3,4,5]. mTOR assembles with alternative binding partners to generate two functionally distinct protein complexes: mTOR complex 1, containing Raptor, and mTOR complex 2, containing Rictor [6,7]. mTORC1 controls cell growth by regulating mRNA translation via phosphorylation of its downstream substrates, ribosomal S6 kinase (S6K) and 4E binding protein 1 (4E-BP1) [8,9]
To elucidate the molecular link between the activation of the Src-related oncogenic pathway and mTOR-mediated tumor progression, we investigated the expression of mTOR complex components and the activity of downstream signaling molecules in human colon and prostate cancer cells in which the Src pathway is activated
Summary
The evolutionarily conserved Ser/Thr kinase mTOR (mammalian target of rapamycin) plays pivotal roles in regulating cell growth, proliferation, and survival [1,2]. MTORC2 regulates cell proliferation, survival and actin cytoskeleton by activating AKT, protein kinase C-α (PKCα) and serum-glucocorticoid-induced protein kinase-1 (SGK1) [7,10,11,12]. Both complexes are activated by growth factor signaling, the signaling cascade leading to activation and regulation of mTORC2 are considerably less known compared to those of mTORC1. In melanoma and colon cancer cells, mTORC2-ribosome association is important in oncogenic PI3K signaling [17] These recent studies indicate that mTORC2 plays important roles in cancer signaling, little is known about the signaling cascade leading to mTORC2 activation and regulation
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