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
Styryl sulfonyl compounds inhibit translation of cyclin D1 in mantle cell lymphoma cells.
Anil Prasad,In-Woo Park,H. Allen,X. Zhang,M. V. R. Reddy,Rengasamy Boominathan,E P Reddy,Jerome E. Groopman +7 more
TL;DR: This paper showed that styryl sulfonyls can cause a rapid decrease of cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels were minimally affected.
Journal ArticleDOI
Molecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment
Hélène Malka-Mahieu,Hélène Malka-Mahieu,Michelle Newman,Michelle Newman,Laurent Désaubry,Laurent Désaubry,Caroline Robert,Stéphan Vagner +7 more
TL;DR: The contribution of the eIF4F complex to tumorigenesis is reviewed, with a focus on its role in chemoresistance as well as the promising use of new small-molecule inhibitors of the complex.
Journal ArticleDOI
Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas.
TL;DR: It seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.
Journal ArticleDOI
Cancer: survival pathways meet their end.
TL;DR: It is proposed that the jugular of cancer-cell survival signalling should be targeted for chemotherapeutic treatment to ensure successful treatment.
Journal ArticleDOI
Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma
TL;DR: The suppression of HCC tumor growth in vivo was enhanced by RAD001 combined with cisplatin, accompanied by a significant increase in the number of apoptotic cells in tumor tissues, demonstrating that inhibition of mTOR suppresses tumor growth and sensitizes tumor cells to chemocytotoxic agents.
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