Article

AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cancer cell (Impact Factor: 23.89). 08/2009; 16(1):21-32. DOI: 10.1016/j.ccr.2009.04.012
Source: PubMed

ABSTRACT Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.

0 Followers
 · 
246 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thyroid receptor-interacting protein 6 (Trip6), a multifunctional protein belonging to the zyxin family of LIM proteins, is involved in various physiological and pathological processes, including cell migration and tumorigenesis. However, the role of Trip6 in neurons remains unknown. Here, we show that Trip6 is expressed in mouse hippocampal neurons and promotes dendritic morphogenesis. Through interaction with the glutamate receptor-interacting protein 1 (GRIP1) and myosin VI, Trip6 is crucial for the total dendritic length and the number of primary dendrites in cultured hippocampal neurons. Trip6 depletion reduces F-actin content and impairs dendritic morphology, and this phenocopies GRIP1 or myosin VI knockdown. Furthermore, phosphorylation of GRIP1(956T) by AKT1 inhibits the interaction between GRIP1 and myosin VI, but facilitates GRIP1 binding to 14-3-3 protein, which is required for regulating F-actin organization and dendritic morphogenesis. Thus, the Trip6-GRIP1-myosin VI interaction and its regulation on F-actin network play a significant role in dendritic morphogenesis. Copyright © 2015 the authors 0270-6474/15/352559-13$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(6):2559-71. DOI:10.1523/JNEUROSCI.2125-14.2015 · 6.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma multiforme (GBM) is the most malignant brain tumor in humans. Previous studies have demonstrated that microRNA plays important roles in the development and proliferation of GBM cells. Here we defined the mechanism by which miR-212-3p regulated the proliferation of GBM. In this study, we showed that miR-212-3p expression was significantly down-regulated and negatively correlated with serum and glucocorticoid-inducible kinase 3 (SGK3) in GBM. Either over-expression of miR-212-3p or silence of SGK3 decreased viability of GBM cells. Moreover, miR-212-3p directly bound to 3'UTR of SGK3 and inhibited its mRNA and protein expression. And over-expression of SGK3 rescued the decreased proliferation of GBM cells induced by miR-212-3p. Importantly, miR-212-3p also suppressed tumor growth in vivo. Collectively, our results demonstrated that miR-212-3p inhibited proliferation of GBM cells by directly targeting SGK3, and could potentially serve as a new therapeutic target for GBM.
    Journal of Neuro-Oncology 02/2015; DOI:10.1007/s11060-015-1736-y · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Melanoma development involves members of the AGC kinase family including AKT, PKC and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in ~70% of human melanomas. The PDK1 substrate SGK3 was determined to be is an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacological inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify melanoma patients for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 02/2015; 75(7). DOI:10.1158/0008-5472.CAN-14-2785 · 9.28 Impact Factor