Open AccessTargeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells
Author(s) -
Hui Liang,
Qi-Li Zheng,
Fang Peng,
Jian Zhang,
Tuo Zhang,
Wei Liu,
Min Guo,
Christopher L. Robinson,
Shuibing Chen,
Xiaoping Chen,
Fangping Chen,
Hui Zeng
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep40361
Subject(s) - myeloid leukemia , pi3k/akt/mtor pathway , cancer research , medicine , gli1 , leukemia , haematopoiesis , pharmacology , population , protein kinase b , progenitor cell , cytarabine , stem cell , apoptosis , immunology , hedgehog signaling pathway , biology , signal transduction , microbiology and biotechnology , biochemistry , environmental health
Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR. Overexpression of GLI1 in AML cells led to increased AKT phosphorylation and decreased drug sensitivity, which was attenuated by GLI1 inhibition. By contrast, neither the expression of GLI1 nor apoptosis in response to Ara-C treatment of AML cells was significantly affected by PI3K inhibition. Furthermore, co-inhibition of GLI1 and PI3K induced apoptosis of hematopoietic stem/progenitor cells (HSPCs), which raised serious concerns about the side effects of this treatment. These results indicated that GLI1 inhibition alone, but not combined inhibition, is sufficient to enhance AML drug sensitivity, which provides a novel therapeutic strategy for AML treatment.