IRF2–INPP4B-mediated autophagy suppresses apoptosis in acute myeloid leukemia cells

Abstract

BackgroundThe present study aimed to investigate the underlying role of interferon-regulatory factor 2 (IRF2)–inositol polyphosphate-4-phosphatase, type-II (INPP4B) axis in the regulation of autophagy in acute myeloid leukemia (AML) cells.MethodsQuantitative real time PCR (QRT-PCR) and western blot were performed to determine the expression levels of IRF2, INPP4B and autophagy-related markers in AML cell lines. Autophagy was assessed by elevated Beclin-1 expression, the conversion of light chain 3 (LC3)-I to LC3-II, downregulated p62 expression and green fluorescent protein (GFP)-LC3 puncta formation. The colony formation and apoptosis assays were performed to determine the effects of IRF2 and INPP4B on the growth of AML cells.ResultsIRF2 and INPP4B were highly expressed in AML cell lines, and were positively correlated with autophagy-related proteins. Overexpression of IRF2 or INPP4B stimulated autophagy of AML cells, whereas inhibition of IRF2 or INPP4B resulted in the attenuation of autophagy. More importantly, IRF2 or INPP4B overexpression reversed autophagy inhibitor, 3-methyladenine (3-MA)-induced proliferation-inhibitory and pro-apoptotic effects, while IRF2 or INPP4B silencing overturned the proliferation-promoting and anti-apoptotic effects of autophagy activator rapamycin.ConclusionIRF2–INPP4B signaling axis attenuated apoptosis through induction of autophagy in AML cells.

IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating β-catenin

“…IRF proteins play pivotal roles in regulating immune response, lymphocyte differentiation, hematopoietic stem cell development and cell proliferation and tumorigenesis [8] . Among this family, IRF2 is associated with the development of various cancers by regulating gene transcription, such as TP53, CXCL3, Bcl-2, and Bax [9] , [10] , [11] . IRF2 is upregulated in pancreatic cancer and HCC cells, and high levels of IRF2 are associated with a worse feature of tumor infiltration depth [ 12 , 13 ].…”

Assessment of INPP4B Expression Level in Acute Myeloid Leukemia Patients and Its Prognostic Significance. An Egyptian Study

“…A possible explanation for decreased CR of patients with high INPP4B expression is that overexpression leads to increased colony forming potential and increased proliferation in AML cell lines (10) . INPP4B overexpression provide the cell a growth advantage, in part by decreased basal apoptotic activity (27) . Also, overexpression in AML cells leads to decreased sensitivity to DNA and ionizing radiation because INPP4B has a direct role in chemotherapy response and is important in mediating cellular response to DNA damaging agents as reported by Dzneladze et al (10) .…”

“…Also, IRF2 might regulate cell autophagy by interacting with INPP4B, and facilitating the development of AML. So, IRF2-INPP4B axis inhibited the apoptosis of AML cells via inducing autophagy in vitro, and thus could be a new target for gene therapy in AML (27) . Accordingly, we assessed the effect of INPP4B overexpression on the treatment outcome and survival in denovo AML patients.…”

Expression and Functional Identification of INPP4B in Gallbladder Cancer Patients and Gallbladder Cancer Cells

“…Previous studies suggested that INPP4B is involved in the apoptosis of tumor cells [15,30]. The apoptosis levels of different lentivirus infection GBC-SD and SGC-996 cells were analysed by ow cytometry.…”