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: 37.91). 04/2006; 6(3):184-92. DOI: 10.1038/nrc1819
Source: PubMed

ABSTRACT 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?

1 Follower
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.69 Impact Factor
  • Source
    • "We further observed that a high dose of TRAIL stimulates the expression of PTEN, which is required for TRAIL to induce a reduction in the levels of pMADD. Although PTEN participates in regulating apoptosis through PI3K‐Akt pathway [Cully et al., 2006], its downstream apoptotic mediators have not been fully delineated. Our present work identified MADD as a mediator of apoptotic signal emanating from PTEN. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitogen-activated kinase activating death domain containing protein (MADD) is abundantly expressed in cancer cells and necessary for maintaining cancer cell survival. However, this survival function of MADD is dependent upon its phosphorylation by protein kinase B (Akt). The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway. The downstream targets of PTEN in triggering apoptosis have not yet been completely identified. Here, we report that MADD can act as a pro-apoptotic factor to initiate apoptosis when its phosphorylation is attenuated by PTEN. Our data show that tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) induced a reduction in MADD phosphorylation with a concomitant up-regulation of PTEN. Knock down of PTEN using a specific siRNA prevented TRAIL-induced reduction in pMADD levels. Surprisingly, Akt non-phopshorylated MADD translocated from the plasma membrane to cytoplasm where it bound to 14-3-3 and displaced 14-3-3 associated Bax, which translocated to mitochondria resulting in cytochrome-C release. Taken together, our data reveal that PTEN can convey the death signal by preventing MADD phosphorylation by Akt. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 02/2014; 115(2). DOI:10.1002/jcb.24657 · 3.37 Impact Factor
  • Source
    • "Both of the above mutations cause constitutive activation of the serine–threonine kinases in the (extracellular signal-regulated kinase) ERK– (mitogen-activated protein kinase ) MAPK pathway, which in turn participate in the regulation of cell growth, survival and angiogenesis, through a series of signaling cascades [18]. Apart from the MAPK pathway, N-Ras also stimulates phosphatidylinisitol-3-kinase (PI3K) to activate AKT, a serine/ threonine-specific protein kinase whose downstream signaling regulates apoptosis, cell proliferation and tumor cell chemoresistance [19] [20] [21]. Cyclin D1 and cyclin-dependent kinases cdk4/cdk6 and cdk2 which are key mediators of cell cycle progression are frequently upregulated in melanoma [2]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The solid melanoma tumor, consists of transformed melanoma cells, and the associated stromal cells including fibroblasts, endothelial cells, immune cells, as well as, soluble macro- and micro-molecules of the extracellular matrix (ECM) forming the complex network of the tumor microenvironement. Heparan sulfate proteoglycans (HSPGs) are an important component of the melanoma tumor ECM. Importantly, there appears to be both a quantitative and qualitative shift in the content of HSPGs, in parallel to the nevi- radial growth phase - vertical growth phase melanoma progression. Moreover, these changes in HSPGs expression are correlated to modulations of key melanoma cell functions. This review will critically discuss the roles of HSPGs/heparin in melanoma development and progression. We have correlated HSPGs' expression and distribution with melanoma cell signaling and functions as well as angiogenesis. The current knowledge of HSPGs/heparin biology in melanoma provides a foundation we can utilize in the ongoing search for new approaches in designing anti-tumor therapy.
    Biochimica et Biophysica Acta 01/2014; 1840(8). DOI:10.1016/j.bbagen.2014.01.031 · 4.66 Impact Factor
Show more


Available from