Cully M, You H, Levine AJ, Mak TW.. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6: 184-192

The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Nature reviews. Cancer (Impact Factor: 37.4). 04/2006; 6(3):184-92. DOI: 10.1038/nrc1819
Source: PubMed


The tumour-suppressor phosphatase with tensin homology (PTEN) is the most important negative regulator of the cell-survival signalling pathway initiated by phosphatidylinositol 3-kinase (PI3K). Although PTEN is mutated or deleted in many tumours, deregulation of the PI3K-PTEN network also occurs through other mechanisms. Crosstalk between the PI3K pathways and other tumorigenic signalling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation. How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?

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    • "In the last few decades, a large number of key molecules has been discovered and studied where they are understood to play an important role in the sensing of chemical stimuli as well as the subsequent polarization, regulation of the actin cytoskeleton and the generation of mechanical forces [46]. Among these molecules are small GTPases [45] [22], PI3K, PTEN, PIPs, [12] [5] [25], Arp2/3 [44] [47] and Cofilin [53] [2]. "
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    ABSTRACT: During cell migration, cells become polarized, change their shape, and move in response to various cues, both internal and external. Many existing mathematical models of cell polarization are formulated in one or two spatial dimensions and hence cannot accurately capture the effect of cell shape, as well as the response of the cell to signals from different directions in a three-dimensional environment. To study those effects, we introduce a three-dimensional reaction-diffusion model of a cell. As some key molecules in cell polarization, such as the small GTPases, can exist both membrane bound and soluble in the cytosol, we first look at the role of cell geometry on the membrane binding/unbinding dynamics of such molecules. We derive quite general conditions under which effective existing one or two-dimensional computational models are valid, and find novel renormalizations of parameters in the effective model. We then extend an established one-dimensional cell polarization pathway in our three-dimensional framework. Our simulations indicate that even in some quasi-one-dimensional scenarios, such as polarization of a cell along a linear growth factor gradient, the cell shape can influence the polarization behavior of the cell, with cells of some shape polarizing more efficiently than those of other shapes. We also investigate the role of the previously ignored membrane unbinding rate on polarization. Furthermore, we simulate the response of the cell when the external signal is changing directions, and we find that more symmetric cells can change their polarized state more effectively towards the new stimulus than cells which are elongated along the direction of the original stimulus.
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    • "On the basis of this knowledge, in the last few years several potent and selective dual PIK3CA/mTOR inhibitors have been generated and carried forward into clinical trials. Unfortunately, severe rash, diarrhea and sometimes difficult to control hyperglycemia have been reported in both mice and human studies [38] [39]. Taselisib is a novel, oral, selective inhibitor of PIK3CA, which spares inhibition of PIK3-beta. "
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    ABSTRACT: Objective To evaluate the efficacy of Taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification. Methods Sensitivity to taselisib was evaluated by flow-cytometry viability assays in vitro against nine primary USC cell lines. Cell cycle distribution and downstream signaling were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry. Preclinical efficacy of taselisib was also evaluated in vivo in a mouse model. Results Four USC cell lines harbored HER2/neu gene amplification by FISH and two of them harbored oncogenic PIK3CA mutations. Taselisib caused a strong differential growth inhibition in both HER2/neu FISH positive and HER2/neu FISH positive/PIK3CA mutated USC cell lines when compared to lines that were FISH negative and PIK3CA wild type (taselisib IC50 mean + SEM = 0.042 + 0.006 μM in FISH + versus 0.38 + 0.06 μM in FISH- tumors, P < 0.0001). Taselisib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and dose-dependent decline in the phosphorylation of S6. Taselisib was highly active at reducing tumor growth in vivo in USC mouse xenografts harboring PIK3CA mutation and overexpressing HER2/neu (P = 0.007). Mice treated with taselisib had significantly longer survival when compared to control mice (P < 0.0001). Conclusions Taselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.
    Gynecologic Oncology 11/2014; 135(2). DOI:10.1016/j.ygyno.2014.08.024 · 3.77 Impact Factor
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    • "The phosphatidylinositol-3-kinase (PI3K) signaling pathway is a crucial regulator of many normal cellular processes, such as cell growth, proliferation, motility, survival, and apoptosis. Deregulation of several components of this pathway, including, PIK3CA, AKT and PTEN have been well documented in a wide range of human cancers 1-3. PIK3CA, a key element of the PI3K/AKT pathway, is located at chromosomal region 3q26.3, and encodes the 110kDa catalytic subunit of class IA (PI3K). "
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    ABSTRACT: The Forkhead transcription factor FOXO1, an important downstream target of phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, regulates cellular homeostasis by maintaining cell proliferation, apoptosis and viability in normal cells. Though, the function and regulation of FOXO1 is well documented in many cancers, the molecular mechanism of its regulation in cervical cancer is largely unknown. In the present study we have investigated the role of PI3K inhibition on FOXO1 regulation. Expression profiling of primary tumors and cell lines show over expression of PIK3CA and AKT1; and down regulation of FOXO1. Lack of FOXO1 promoter methylation and inability of hypomethylating drug 5-Aza-2'-deoxycytidine and HDAC inhibitor trichostatin A to reactivate FOXO1 expression suggest that loss of FOXO1 expression is due to mechanisms other than promoter methylation/acetylation. Inhibition of PI3K by LY294002 decreased the level of p-AKT1 and activated FOXO1 transcription factor. We demonstrate that activation of FOXO1 induces apoptosis, cell proliferation arrest, and decreased cell viability in cervical cancer cell lines. Our data suggest that frequent down regulation of FOXO1 and its functional inactivation may be due to post-translational modifications in cervical cancer. Together, these observations suggest that activation of FOXO1 and its nuclear sequestration is critical in the regulation of cell proliferation, cell viability and apoptosis in cervical cancer. Hence, PI3K/AKT pathway may be a potential molecular target for cervical cancer therapy.
    Journal of Cancer 08/2014; 5(8):655-62. DOI:10.7150/jca.6554 · 3.27 Impact Factor
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