Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia

Autor: Ecker, Veronika, Stumpf, Martina, Brandmeier, Lisa, Neumayer, Tanja, Pfeuffer, Lisa, Engleitner, Thomas, Ringshausen, Ingo, Nelson, Nina, Jücker, Manfred, Wanninger, Stefan, Zenz, Thorsten, Wendtner, Clemens, Manske, Katrin, Steiger, Katja, Rad, Roland, Müschen, Markus, Ruland, Jürgen, Buchner, Maike
Přispěvatelé: Ringshausen, Ingo [0000-0002-7247-311X], Zenz, Thorsten [0000-0001-7890-9845], Steiger, Katja [0000-0002-7269-5433], Rad, Roland [0000-0002-6849-9659], Müschen, Markus [0000-0002-6064-8613], Ruland, Jürgen [0000-0002-8381-3597], Buchner, Maike [0000-0002-4196-096X], Apollo - University of Cambridge Repository, University of Zurich, Buchner, Maike
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Chronic lymphocytic leukaemia
Cancer therapy
Cell Survival
Science
610 Medicine & health
1600 General Chemistry
Mice
Transgenic
13
Oxidative Phosphorylation
38
13/1
Mice
Phosphatidylinositol 3-Kinases
1300 General Biochemistry
Genetics and Molecular Biology
immune system diseases
Cell Line
Tumor
hemic and lymphatic diseases
Animals
Humans
Transplantation
Homologous
RNA-Seq
RNA
Small Interfering
13/89
neoplasms
692/4028/67/1059
64
Cell Death
article
64/110
Immunohistochemistry
Leukemia
Lymphocytic
Chronic
B-Cell
Xenograft Model Antitumor Assays
3100 General Physics and Astronomy
Mitochondria
13/31
631/67/1990/283/1895
Phosphatidylinositol-3
4
5-Trisphosphate 5-Phosphatases
10032 Clinic for Oncology and Hematology
13/51
13/95
Disease Progression
Reactive Oxygen Species
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021)
Nature Communications
ISSN: 2041-1723
Popis: Current therapeutic approaches for chronic lymphocytic leukemia (CLL) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the phosphatidylinositol-3-phosphate/AKT (PI3K/AKT)-signaling pathway may be leveraged to trigger CLL cell death. Though counterintuitive, our data show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SH2-containing-inositol-5′-phosphatase-1 (SHIP1) induces acute cell death in CLL cells. Our mechanistic studies reveal that increased AKT activity upon inhibition of SHIP1 leads to increased mitochondrial respiration and causes excessive accumulation of reactive oxygen species (ROS), resulting in cell death in CLL with immunogenic features. Our results demonstrate that CLL cells critically depend on mechanisms to fine-tune PI3K/AKT activity, allowing sustained proliferation and survival but avoid ROS-induced cell death and suggest transient SHIP1-inhibition as an unexpectedly promising concept for CLL therapy.
Current therapeutic approaches in chronic lymphocytic leukemia (CLL) focus on the suppression of PI3K/AKT signaling. Here, the authors show that CLL cells are vulnerable to hyperactivation of the PI3K/AKT signaling pathway and suggest this as a promising concept for CLL therapy.
Databáze: OpenAIRE
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