ARPC2 Targeting Inhibition Progress the Proliferation Suppression of Acute Myeloid Leukemia through PI3K-AKT Pathway

Background: Acute myeloid leukemia (AML) is a hematologic malignancy originating from the bone marrow, and its high degree of heterogeneity has led to differences in clinical treatment and prognosis. Therefore, there is an urgent need to find new potential biological targets to guide clinical treatment. Actin related protein 2/3 complex subunit 2 (ARPC2) is an actin-binding component involved in the regulation of actin polymerization. Benproperine phosphate and pimozide have been confirmed to be the target inhibitors of ARPC2. However, the role of ARPC2 and the target drugs, benproperine phosphate and pimozide, is poorly known. Therefore, this study intends to explore the expression characteristic and prognosis significance of ARPC2 in AML, as well as to explore the effect by target inhibition of ARPC2 by benproperine phosphate and pimozide in AML .

Methods: Threedataset of AML patients were obtained from TCGA, GTEx and GEO. The relationship between ARPC2 expression and survival of AML patients was analyzed by Kaplan-Meier curves and Cox regression. The main pathways of ARPC2 in AML were analyzed by Gene Set Enrichment Analysis (GSEA) . The toxic effects of benproperine phosphate and pimozide in AML cells were examined by MTS assay. The effects of target inhibition of ARPC2 by benproperine phosphate and pimozide in AML cells were analyzed by Real-time fluorescence quantitative PCR (RT-qPCR) . Cell proliferation was detected by MTS assay, apoptosis was detected by flow cytometry, and the expression of relevant proteins was detected by Western Blot (WB).

Results: Combining TCGA, GTEx and GEO databases, we found that ARPC2 was highly expressed in AML patients (P<0.001). Survival analysis showed that AML patients with high ARPC2 expression had poor prognosis (P<0.05). Univariate and multivariate Cox regression analyses showed that high expression of ARPC2 was an independent poor prognostic factor for AML (P<0.05). GSEA analyses showed that PI3K-AKT pathway, MTORC1 signaling pathway, oxidative phosphorylation and oxidative stress were significantly activated in ARPC2 high expression group. Targeting ARPC2 by benproperine phosphate and pimozide had a significant cytotoxic effect on AML cells with significant concentration and time dependence. Through WB analysis, we found that both benproperine phosphate and pimozide could suppress the apoptosis proteins, such as BCL-2. They could also suppress the PI3K and AKT proteins, which are the key proteins of PI3K/AKT pathway, and this consistent with GSEA analysis.

Conclusion: High expression of ARPC2 is an independent adverse prognostic factor for AML patients. Benproperine phosphate and pimozide can inhibit the proliferation and promote apoptosis of AML cells by targeting ARPC2 through PI3K-AKT pathway, which may provide a new idea for the future targeted therapy of AML.

No relevant conflicts of interest to declare.