Inhibition of the Akt/survivin pathway synergizes the antileukemia effect of nutlin-3 in acute lymphoblastic leukemia cells
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt and p53 pathways play antiapoptotic and proapoptotic roles in cell death, respectively. Cancer cell growth and progression are associated with high levels of PI3K/Akt activation by loss of PTEN expression and the inactivation of p53 by MDM2 overexpression. We report that inhibition of PI3K/Akt, either by the PI3K inhibitor Ly294002 or by expression of PTEN, synergized the ability of the MDM2 antagonist nutlin-3 to induce apoptosis in acute lymphoblastic leukemia (ALL). We used a set of ALL cell lines with wild-type p53 and MDM2 overexpression, but different status of PTEN expression/PI3K/Akt activation, to test the ability of nutlin-3 to induce p53 and apoptosis. Nutlin-3 activated p53 in all the ALL cell lines; however, induction of apoptosis was dependent on PTEN status. Nutlin-3 induced potent apoptosis in cells with PTEN expression but not in those without PTEN, suggesting that PTEN/PI3K/Akt pathway may play a role in this process. Furthermore, nutlin-3 significantly down-regulated survivin expression in PTEN-positive cells but not in PTEN-negative cells. When these nutlin-3–resistant cells were either pretransfected with the PTEN gene or simultaneously treated with the PI3K inhibitor Ly294002, survivin was down-regulated and sensitivity to nutlin-3 was increased. Furthermore, direct silencing of survivin by small interfering RNA also increased the proapoptotic effect of nutlin-3 on the PTEN-negative, nutlin-3–resistant ALL cells. Our results suggest that Akt-mediated survivin up-regulation in PTEN-negative ALL cells may counteract the proapoptotic effect of nutlin-3, and indicate that a combination of MDM2 antagonist and PI3K/Akt inhibitor may be a promising approach for treating refractory ALL. [Mol Cancer Ther 2008;7(5):1101–9]
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Blocking PI3K-AKT signaling makes acute lymphoblastic leukaemia cell lines more sensitive to p53 activation by nutlin 3a.
“inhibition of the PI3K–AKT pathway sensitizes acute lymphoblastic leukaemia (ALL) cell lines to nutlin 3a-induced p53 activation127.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [127]
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Molecular Regulators of Stem Cell Fate and Tumor Development in the Cerebellum
Brun, S. N. (2014) · DukeSpace (Duke University)
- Authors
- Zhu, N., Gu, L., Li, F., & Zhou, M.
- Affiliations
- Emory University (US)
- Roswell Park Comprehensive Cancer Center (US)
- Venue
- Molecular Cancer Therapeutics
- Published
- 2008-05-01
- Volume
- 7
- Issue
- 5
- Pages
- 1101-1109
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2022070430
- Cited by
- 42
- References
- 48
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 2 · 2013: 4 · 2012: 3
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA123490)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- Nutlin-3, acute lymphoblastic leukemia, PI3K/Akt signaling, PTEN, MDM2 inhibitors, survivin, p53 activation, apoptosis, drug synergy, combination therapy, drug resistance
- MeSH terms
- Survivin, Acute Disease, Antineoplastic Combined Chemotherapy Protocols, Chromones, Drug Synergism, Humans, Imidazoles, Microtubule-Associated Proteins, Morpholines, Neoplasm Proteins, Piperazines, Transfection, Tumor Cells, Cultured, Signal Transduction, Cell Death, Apoptosis, RNA, Small Interfering, Inhibitor of Apoptosis Proteins, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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