TY - JOUR
T1 - Targeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia
AU - Evangelisti, Cecilia
AU - Chiarini, Francesca
AU - Cappellini, Alessandra
AU - Paganelli, Francesca
AU - Fini, Milena
AU - Santi, Spartaco
AU - Martelli, Alberto M
AU - Neri, Luca M
AU - Evangelisti, Camilla
N1 - © 2020 Wiley Periodicals, Inc.
PY - 2020/6
Y1 - 2020/6
N2 - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, β-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β-catenin pathway through ICG-001, a CBP/β-catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK-474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T-ALL cells. ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β-catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-ALL settings.
AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, β-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β-catenin pathway through ICG-001, a CBP/β-catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK-474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T-ALL cells. ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β-catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-ALL settings.
KW - PI3K/Akt/mTOR
KW - T-ALL
KW - Wnt/β-catenin
KW - combination therapy
KW - hypoxia
KW - targeted therapy
U2 - 10.1002/jcp.29429
DO - 10.1002/jcp.29429
M3 - Article
C2 - 31904116
VL - 235
SP - 5414
EP - 54298
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
SN - 1097-4652
IS - 6
ER -