Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells

Abstract

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.

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

“…Gli1 can be regulated by specific serine/threonine kinases (34,(36)(37)(38), and we have demonstrated that DGT inhibits GSK3b activity, which are known to be associated with osteosarcoma progression and poor patient outcome. Therefore, we hypothesized that GSK3b activity is involved in DGT-induced Gli1 repression in osteosarcoma.…”

Mesenchymal stem cells targeting PI3K/AKT pathway in leukemic model

“…47 Meanwhile, sustained activation of the PI3K/AKT pathway accompanied with deletion of PTEN has been identified in different types of leukemia. 6 Targeting the PI3K/AKT/mTOR pathway may have pro-apoptotic and anti-proliferative effects on hematological malignancies through simultaneous targeting of Bcl-2/Bcl-xL pathways represent an effective anti-leukemic strategy via down-regulation of Mcl-1 and up-regulation/activation of Bak, Bax, Bim, and Bad. 48 Many appearances properties of MSCs that include anti-apoptosis, growth factor production, neuroprotection, anti-fibrosis, and chemo-attraction provide a broad spectrum for its using in disease therapies.…”

“…5 Acute amyloid leukemia involving different signaling pathways are expected to be involved in the clinical treatment of acute amyloid leukemia. 6 The PI3K/AKT/mTOR signaling pathways are detectable and activated in most cases of AML. Inhibition of PI3K/AKT or mTORC1 signaling pathways suppresses the proliferation in vitro.…”

Advances in Acute Myeloid Leukemia Stem Cells

“…The PI3K/Akt pathway is an intracellular pathway that plays a critical role in apoptosis and cancer, whose components are often altered in cancer, leading to dysregulated apoptosis and chemoresistance [78]. Chen et al demonstrated that the PI3K inhibitor LY294002 can directly target LSCs without adverse reactions to normal HSCs, and they found that PI3K and NF-κB may coexist in the same signaling pathway [79].…”