Involvement of Akt-1 and mTOR in Sensitivity of Breast Cancer to Targeted Therapy
| Autor: | Stephen L. Abrams, William H. Chappell, Ferdinando Nicoletti, Melissa L. Sokolosky, Franca Stivala, Massimo Libra, Kristin Stadelman, Richard A. Franklin, James A. McCubrey, Linda S. Steelman, Alberto M. Martelli, Lyudmyla Drobot |
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| Přispěvatelé: | Sokolosky M.L., Stadelman K.M., Chappell W.H., Abrams S.L., Martelli A.M., Stivala F., Libra M., Nicoletti F., Drobot L.B., Franklin R.A., Steelman L.S., McCubrey J.A. |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_treatment
Antineoplastic Agents Breast Neoplasms Targeted therapy 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Line Tumor medicine Humans PTEN Molecular Targeted Therapy skin and connective tissue diseases Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Etoposide 030304 developmental biology Sirolimus 0303 health sciences biology TOR Serine-Threonine Kinases Akt RPTOR medicine.disease Research Papers 3. Good health Tamoxifen Oncology Doxorubicin Drug Resistance Neoplasm 030220 oncology & carcinogenesis Drug resistance mTOR biology.protein Cancer research Female Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Scopus-Elsevier Oncotarget |
| Popis: | Melissa L. Sokolosky 1,2 , Kristin M. Stadelman 1,2 , William H. Chappell 1 , Stephen L. Abrams 1 , Alberto M. Martelli 3,4 , Franca Stivala 5 , Massimo Libra 5 , Ferdinando Nicoletti 5 , Lyudmyla B. Drobot 6 , Richard A. Franklin 1 Linda S. Steelman 1 , and James A. McCubrey 1 1 Department of Microbiology & Immunology Brody School of Medicine at East Carolina University Greenville, NC 27858 USA 2 These two authors contributed equally to the studies. 3 Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore Universita di Bologna, Bologna, Italy 4 IGM-CNR, Sezione di Bologna, C/o IOR, Bologna, Italy 5 Department of Biomedical Sciences University of Catania, Catania, Italy 6 Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine Received: June 23, 2011; Accepted: July 1, 2011; Published: July 1, 2011; Keywords: Akt, mTOR, Targeted Therapy, Drug Resistance Correspondence: James A. McCubrey, email: // // Abstract Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascades. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [∆Akt-1(CA)] were more resistant to doxorubicin, etoposide and 4-OH-tamoxifen (4HT) than cells lacking ∆Akt-1(CA). Cells which expressed ∆Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC 50 s for doxorubicin, etoposide and 4HT in the cells which expressed ∆Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies. |
| Databáze: | OpenAIRE |
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