The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia

Polak, Roel; Buitenhuis, Miranda

doi:10.1182/blood-2011-07-366203

Cited by 123 publications

(141 citation statements)

References 170 publications

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“…Alterations in the PI3K/Akt axis are known to be both associated with and causal of oncogenesis (33,34). Although cellular transformation has been most frequently related to the dysregulation of protein translation as a consequence of mTOR activation (35,36), the role of Akt in enhancing ribosomal biogenesis is receiving increasing attention (3,37).…”

Section: Discussionmentioning

confidence: 99%

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Nguyen

Mitchell

2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Ribosomal proteins are synthesized in the nucleolus under the control of a number of repetitive DNA elements and are required for cell proliferation. Cancer cells frequently contain mutations that activate the phosphoinositide 3-kinase/Akt signaling pathway. This study shows that activation of Akt enhances the transcription of ribosomal genes by stabilizing a protein, transcription initiation factor I (TIF-IA), which is essential for the transcription of ribosomal DNA. Activated Akt also increases ribosomal RNA synthesis by phosphorylating casein kinase 2, which in turn phosphorylates and enhances the activity of TIF-IA. These results demonstrate new mechanisms by which the activation of Akt can promote tumor cell proliferation and further support the targeting of activated Akt as a potential therapy for certain cancers.

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Section: Discussionmentioning

confidence: 99%

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Nguyen

Mitchell

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…11 Thus, small-molecule inhibitors of Akt have a great potential for novel forms of cancer treatment. 12,13 PI3K/Akt activation is detected in about 85% of T-ALL patients and portends a poorer prognosis. 14,15 Moreover, when a constitutively active, myristoylated allele of Akt was introduced into murine hematopoietic cells, mice developed a T-cell lymphoma with high frequency (65%).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

et al. 2012

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“…[4][5][6] Since aberrant regulation of the PI3K pathway has been frequently observed in leukemic cells (presumably due to activating signals from the microenvironment rather than mutations in genes belonging to the pathway), PI3K is considered to be a promising target for therapy. 4,6,7 Preclinical experiments indicated that the PI3K inhibitors (PI3Ki) LY294002 and wortmannin induced apoptosis in leukemic cells, but they were also toxic to normal cells, probably because of the low specificity and inhibition of other kinases. Recently, selective isoform-specific inhibitors, such as the PI3Kδ inhibitor CAL-101, have appeared to affect survival of chronic lymphocytic leukemia cells and CAL-101 has entered phase I/II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…It is an important mediator of drug resistance and it has been described to be frequently altered in a wide variety of types of human cancer. [4][5][6] Two subclasses of PI3K have been related to cancer: class IA (p110a, b and δ isoforms of the catalytic subunit) is predominantly activated by tyrosine kinases, and class IB (p110γ isoform) is mainly activated by G-protein-coupled receptors. Upon extracellular stimulation, PI3K phosphorylate phosphatidylinositol 4,5 biphosphate (PIP2) to form phosphatidylinositol 3,4,5 triphosphate (PIP3).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

et al. 2012

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Peripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol-3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol-3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.068510 Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

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The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia

Cited by 123 publications

References 170 publications

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

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