Journal ArticleDOI
Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.
Hans-Guido Wendel,Elisa de Stanchina,Jordan S. Fridman,Jordan S. Fridman,Abba Malina,Sagarika Ray,Scott C. Kogan,Carlos Cordon-Cardo,Jerry Pelletier,Scott W. Lowe +9 more
Reads0
Chats0
TLDR
It is shown that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects.Abstract:
Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.read more
Citations
More filters
Journal ArticleDOI
On translational regulation and EMT.
TL;DR: The possibility that progression of primary epithelial tumors into a motile mesenchymal-like phenotype during the invasive phase of metastasis is driven, in part, by a switch from cap-dependent to cap-independent translation is discussed.
Journal ArticleDOI
A Molecular Link between AKT Regulation and Chemotherapeutic Response
TL;DR: Pei et al. show that FKBP51 negatively regulates AKT through the phosphatase PHLPP, which appears to be a determinant of chemosensitivity in cancer cells.
Journal ArticleDOI
Probing the binding mechanism of Mnk inhibitors by docking and molecular dynamics simulations.
Srinivasaraghavan Kannan,Anders Poulsen,Hai Yan Yang,Melvyn Ho,Shi Hua Ang,Tan Sum Wai Eldwin,Duraiswamy Athisayamani Jeyaraj,Lohitha Rao Chennamaneni,Boping Liu,Jeffrey Hill,Chandra S. Verma,Chandra S. Verma,Chandra S. Verma,Kassoum Nacro +13 more
TL;DR: The models suggest that the activities of these small molecule inhibitors arise from interactions with multiple residues in the active sites, particularly with the hydrophobic residues.
Journal ArticleDOI
BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors.
Enrico Derenzini,Enrico Derenzini,Patrizia Mondello,Tatiana Erazo,Ana Portelinha,Yuxuan Liu,Mary I. Scallion,Zahra Asgari,John Philip,Patrick Hilden,Debora Valli,Alessandra Rossi,Hakim Djaballah,Ouathek Ouerfelli,Elisa de Stanchina,Venkatraman E. Seshan,Ronald C. Hendrickson,Anas Younes +17 more
TL;DR: Prosurvival feedbacks induced by BETi involving GSK3β regulation, providing a mechanistic rationale for combination strategies in lymphoma, are revealed.
Journal ArticleDOI
Mst1, RanBP2 and eIF4G are new markers for in vivo PI3K activation in murine and human prostate
Oliver Renner,Jesús Fominaya,Soledad Alonso,Carmen Blanco-Aparicio,Juan F.M. Leal,Amancio Carnero +5 more
TL;DR: New markers for in vivo PI3K activation in prostate are reported and it is described that the phosphorylation of AKT and eIF4G, as well as the elevation of the Mst1 and RanBP2 protein levels, can be inhibited in vivo in transgenic animals by thePI3K inhibitor LY294002.
References
More filters
Journal ArticleDOI
The hallmarks of cancer.
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
Journal ArticleDOI
The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
Igor Vivanco,Charles L. Sawyers +1 more
TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.
Journal ArticleDOI
Cellular survival: a play in three Akts
TL;DR: The mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI 3K/ c-AKT pathway promotes cell survival, and the current spectrum of c- akt targets and their roles in mediating c- Akt-dependent cell survival are reviewed.
Journal ArticleDOI
Identification of a candidate tumour suppressor gene, MMAC1 , at chromosome 10q23.3 that is mutated in multiple advanced cancers
Peter A. Steck,Mark A. Pershouse,Samar A. Jasser,W. K. A. Yung,Huai Lin,Azra H. Ligon,Lauren A. Langford,Michelle Baumgard,T. Hattier,Thaylon Davis,Cheryl Frye,Rong Hu,Bradley D. Swedlund,David H. F. Teng,Sean V. Tavtigian +14 more
TL;DR: The results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.
Journal ArticleDOI
NF-κB in cancer: from innocent bystander to major culprit
TL;DR: Recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development.
Related Papers (5)
The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
Igor Vivanco,Charles L. Sawyers +1 more