The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells - PubMed (original) (raw)

The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells

Omer H Yilmaz et al. Blood Cells Mol Dis. 2008 Jul-Aug.

Abstract

The identification of cancer stem cells in leukemia, breast, brain, colon, and other cancers suggests that many tumors are maintained by stem cells in much the same way as normal tissues are maintained. Because cancer stem cells share remarkable phenotypic and functional similarities with normal stem cells, it may be difficult to identify therapeutic approaches to kill cancer stem cells without killing the normal stem cells in the same tissue. Yet in certain tissues, like the hematopoietic system and gut epithelium, this will be critical as regenerative capacity in these tissues is acutely required for life. Components of the PI-3kinase pathway, including Akt, mTor and FoxO are critical regulators of both normal stem cell function and tumorigenesis. Intriguingly, inactivation of some pathway components, like Pten, has opposite effects on normal hematopoietic stem cells (HSCs) and leukemia-initiating cells. This raises the possibility that drugs targeting this pathway could be more effective at eliminating cancer stem cells while being less toxic against normal stem cells.

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Figures

Figure 1. The PI-3kinase pathway and possible mechanisms of HSC depletion

Activated receptor tyrosine kinases (RTKs) signal through scaffolding adaptors (e.g. IRS-1) that activate PI-3kinase. Pten suppresses the activation of Akt. Deletion of Pten leads to the hyperactivation Akt, loss of FoxO function, and activation of the mTorc1 and mTorc2 complexes. Important target genes of FoxO include regulators of cell death (e.g. Bim-1 and Fas-L), cell cycle progression (e.g. p21Cip1 and p27Kip1), and ROS detoxification (e.g. catalase and MnSOD). There are multiple pathways downstream of activated mTorc1, including S6 kinase (which regulates protein synthesis and ribosome biogenesis) and 4E-BP1 (which regulates cap-dependent translation). Rapamycin treatment reduces the activation of S6K, reduces the inhibition of 4E-BP and rescues the function of _Pten_-deficient HSCs. Although Akt activation leads to mTorc1 activation, mTorc1 activation can reduce Akt activation by a negative feedback mechanism involving S6K. Rapamycin treatment can disrupt this negative feedback mechanism and therefore increase Akt signaling, which affects the many effectors that lie downstream of Akt. Downstream targets of mTorc2 include kinases such as PKCα Rho, Rac, and Akt. Prolonged rapamycin treatment has been demonstrated to also inhibit assembly of the mTorc2 complex by sequestering mTor, leading to decreased Akt activation. This finding raises the possibility that rapamycin treatment may also restore FoxO function in _Pten_-deficient HSCs by inhibiting mTorc2. Abbreviations (RTKs, receptor tyrosine kinases; IRS-1, insulin receptor substrate-1; PI-3K, phosphatidylinositol-3-OH kinase; Fas-L, Fas ligand; MnSOD, manganese superoxide dismutase; mTorc1, mTor complex 1; mTorc2, mTor complex 2; 4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; eIF4E, eukaryotic translation initiation factor 4E; S6K, S6 kinase; PKCα, protein kinase C alpha)

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The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells - PubMed (original) (raw)