The role of PTEN signaling perturbations in cancer and in targeted therapy

Keniry, Megan; Parsons, Ramon

doi:10.1038/onc.2008.248

Cited by 328 publications

(235 citation statements)

References 130 publications

(153 reference statements)

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“…PTEN encodes a lipid and protein phosphatase whose primary lipid substrate is PtdIns(3,4,5)P 3 . 2,[19][20][21][22] The purported protein substrate(s) of PTEN are more varied and controversial, including focal adhesion kinase, the Shc exchange protein and the transcriptional regulators ETS-2, CREB and Sp1 and the platelet-derived growth factor receptor as well as others. 23,24 PTEN has been recently shown to have nuclear activities and it may serve to dephosphorylate some transcription factors such as ETS-2, Sp1, CREB and others.…”

Section: Introductionmentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…Gain-of-function mutations in PIK3CA, the gene encoding the class I A PI3K catalytic subunit p110α, are frequently present in multiple human tumors (8). Second, the PIP3 phosphatase PTEN is a tumor suppressor frequently inactivated by mutation, gene deletion, and promoter methylation (9). Further, PI3K is potently activated by oncogenes like mutant Ras and tyrosine kinases such as Bcr-Abl, HER2 (ErbB2), MET, and KIT, among others (1).…”

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confidence: 99%

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Chakrabarty

Sánchez

Kuba

et al. 2011

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

313

267

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We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2 + cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.signaling | targeted therapy P I3K transmits signals from ligand-activated receptor tyrosine kinases (RTKs) to intracellular molecules that regulate growth, metabolism, cell size, motility, and survival. In turn, PI3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate to produce the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) (1, 2). Several pleckstrin homology domaincontaining proteins, including AKT and PDK1, bind to PIP3 at the plasma membrane. Phosphorylation of AKT at T308 by PDK1 and at S473 by a complex involving mTOR/Rictor (i.e., TORC2) results in the full activation of this enzyme. AKT facilitates survival and cell cycle entry by phosphorylation of proteins including GSK3α/β, FoxO transcription factors, MDM2, BAD, and p27 KIP1 (3). In addition, AKT regulates protein synthesis and cell growth via activation of the mTOR/Raptor (i.e., TORC1) complex (4, 5).PI3K/AKT is arguably the most commonly altered pathway in human cancers (6, 7). Gain-of-function mutations in PIK3CA, the gene encoding the class I A PI3K catalytic subunit p110α, are frequently present in multiple human tumors (8). Second, the PIP3 phosphatase PTEN is a tumor suppressor frequently inactivated by mutation, gene deletion, and promoter methylation (9). Further, PI3K is potently activated by oncogenes like mutant Ras and tyrosine kinases such as Bcr-Abl, HER2 (ErbB2), MET, and KIT, among others (1). Therefore, a large group of tumors with molecular alterations in the PI3K/AKT pathway is therapeutically targetable with PI3K inhibitors.Several PI3K pathway antagonists have been developed. These include ATP mimetics that bind reversibly in the ATP...

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“…Therefore, AKT is activated by PI3K, which generates phosphatidylinositol 3, 4, 5-trisphosphate, and is negatively regulated by phospholipid phosphatases PTEN. 4 Hyperactivated AKT provides protection from apoptosis and promotes uncontrolled cell cycle progression. 5 However, it has recently been shown that AKT activity increases with cellular senescence, and that inhibition of AKT extends the lifespan of primary cultured human endothelial cells.…”

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confidence: 99%

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

et al. 2010

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Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTENproficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.

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The role of PTEN signaling perturbations in cancer and in targeted therapy

Cited by 328 publications

References 130 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

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