An ARC-Regulated IL1β/Cox-2/PGE2/β-Catenin/ARC Circuit Controls Leukemia-Microenvironment Interactions and Confers Drug Resistance in AML

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-03, Vol.79 (6), p.1165-1177
• Main Authors: Carter, Bing Z, Mak, Po Yee, Wang, Xiangmeng, Tao, Wenjing, Ruvolo, Vivian, Mak, Duncan, Mu, Hong, Burks, Jared K, Andreeff, Michael
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; beta Catenin - genetics; beta Catenin - metabolism; Biomarkers, Tumor - metabolism; Cell Proliferation; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cytoskeletal Proteins - pharmacology; Dinoprostone - pharmacology; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Nerve Tissue Proteins - pharmacology; Oxytocics - pharmacology; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-0921

The apoptosis repressor with caspase recruitment domain (ARC) protein is a strong independent adverse prognostic marker in acute myeloid leukemia (AML). We previously reported that ARC regulates leukemia-microenvironment interactions through the NFκB/IL1β signaling network. Malignant cells have been reported to release IL1β, which induces PGE2 synthesis in mesenchymal stromal cells (MSC), in turn activating β-catenin signaling and inducing the cancer stem cell phenotype. Although Cox-2 and its enzymatic product PGE2 play major roles in inflammation and cancer, the regulation and role of PGE2 in AML are largely unknown. Here, we report that AML-MSC cocultures greatly increase Cox-2 expression in MSC and PGE2 production in an ARC/IL1β-dependent manner. PGE2 induced the expression of β-catenin, which regulated ARC and augmented chemoresistance in AML cells; inhibition of β-catenin decreased ARC and sensitized AML cells to chemotherapy. NOD/SCIDIL2RγNull-3/GM/SF mice transplanted with ARC-knockdown AML cells had significantly lower leukemia burden, lower serum levels of IL1β/PGE2, and lower tissue human ARC and β-catenin levels, prolonged survival, and increased sensitivity to chemotherapy than controls. Collectively, we present a new mechanism of action of antiapoptotic ARC by which ARC regulates PGE2 production in the tumor microenvironment and microenvironment-mediated chemoresistance in AML. The antiapoptotic protein ARC promotes AML aggressiveness by enabling detrimental cross-talk with bone marrow mesenchymal stromal cells.