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. 2010 Aug 18;2(3):1576-96.
doi: 10.3390/cancers2031576.

The emerging role of the phosphatidylinositol 3-kinase/ akt/mammalian target of rapamycin signaling network in cancer stem cell biology

Alberto M Martelli  1 , Camilla Evangelisti, Francesca Chiarini, Cecilia Grimaldi, James A McCubrey
Affiliations

The emerging role of the phosphatidylinositol 3-kinase/ akt/mammalian target of rapamycin signaling network in cancer stem cell biology

Alberto M Martelli et al. Cancers (Basel). .

Abstract

The cancer stem cell theory entails the existence of a hierarchically organized, rare population of cells which are responsible for tumor initiation, self-renewal/maintenance, and mutation accumulation. The cancer stem cell proposition could explain the high frequency of cancer relapse and resistance to currently available therapies. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway regulates a wide array of physiological cell functions which include differentiation, proliferation, survival, metabolism, autophagy, and motility. Dysregulated PI3K/Akt/mTOR signaling has been documented in many types of neoplasias. It is now emerging that this signaling network plays a key role in cancer stem cell biology. Interestingly, cancer stem cells displayed preferential sensitivity to pathway inhibition when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling pathways between neoplastic stem cells and healthy stem cells could be identified. In this review, we present the evidence which links the signals emanating from the PI3K/Akt/mTOR cascade with the functions of cancer stem cells, both in solid and hematological tumors. We then highlight how targeting PI3K/Akt/mTOR signaling with small molecules could improve cancer patient outcome.

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Figures

Figure 1
Figure 1
The PI3K/Akt/mTOR signaling pathway. RTKs, GPCRs, and Ras stimulate class I PI3K activity. PI3K generates PtdIns 3,4,5P3 from PtdIns 4,5, P2. PtdIns 3,4,5P3 attracts to the plasma membrane PDK1 which phosphorylates Akt on Thr 308. Full Akt activation requires Ser 473 phosphorylation by mTORC2. Active Akt inhibits TSC2 activity through direct phosphorylation. TSC2 is a GAP that functions in association with TSC1 to inactivate the small G protein Rheb. Akt-driven TSC1/TSC2 complex inactivation allows Rheb to accumulate in a GTP-bound state. Rheb-GTP upregulates the protein kinase activity of mTORC1. However, other signals impinge on mTORC1, including the Ras/Raf/MEK/ERK1/2/p90RSK pathway, the AMPK network, RAG 1/2, REDD 1/2, Wnt/GSK3β. mTORC1 targets p70S6K 1/2 and 4E-BP1 which are critical for translation. S6RP, eIF4B, and PCCD4 are targets of p70S6K 1/2. mTORC2 regulates actin polymerization and phosphorylates PKCα and SGK1. Arrows indicate activating events, whereas perpendicular lines highlight inhibitory events.
Figure 2
Figure 2
A schematic of mTOR structure. Some of the proteins interacting with mTOR domains are highlighted. The FRB domain is where the FKBP12 and rapamycin/rapalog complex binds, which is within the region that binds FKBP38.
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