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Role of Signal Regulatory Protein ? in Arsenic Trioxide-induced Promyelocytic Leukemia Cell Apoptosis.

ABSTRACT: Signal regulatory protein ? (SIRP?) has been shown to operate as a negative regulator in cancer cell survival. The mechanism underneath such function, however, remains poorly defined. In the present study, we demonstrate that overexpression of SIRP? in acute promyelocytic leukemia (APL) cells results in apoptosis possibly via inhibiting the ?-catenin signaling pathway and upregulating Foxo3a. Pharmacological activation of ?-catenin signal pathway attenuates apoptosis caused by SIRP?. Interestingly, we also find that the pro-apoptotic effect of SIRP? plays an important role in arsenic trioxide (ATO)-induced apoptosis in APL cells. ATO treatment induces the SIRP? protein expression in APL cells and abrogation of SIRP? induction by lentivirus-mediated SIRP? shRNA significantly reduces the ATO-induced apoptosis. Mechanistic study further shows that induction of SIRP? protein in APL cells by ATO is mediated through suppression of c-Myc, resulting in reduction of three SIRP?-targeting microRNAs: miR-17, miR-20a and miR-106a. In summary, our results demonstrate that SIRP? inhibits tumor cell survival and significantly contributes to ATO-induced APL cell apoptosis.

SUBMITTER: Pan C

PROVIDER: S-EPMC4806322 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Role of Signal Regulatory Protein α in Arsenic Trioxide-induced Promyelocytic Leukemia Cell Apoptosis.

Pan Chaoyun C Zhu Dihan D Zhuo Jianjiang J Li Limin L Wang Dong D Zhang Chen-Yu CY Liu Yuan Y Zen Ke K

Scientific reports 20160324

Signal regulatory protein α (SIRPα) has been shown to operate as a negative regulator in cancer cell survival. The mechanism underneath such function, however, remains poorly defined. In the present study, we demonstrate that overexpression of SIRPα in acute promyelocytic leukemia (APL) cells results in apoptosis possibly via inhibiting the β-catenin signaling pathway and upregulating Foxo3a. Pharmacological activation of β-catenin signal pathway attenuates apoptosis caused by SIRPα. Interesting ...[more]

PMID: 27010069

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Project description:BackgroundArsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO.MethodsA total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients' plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+?3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method.ResultsThe study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIII in patient's urine (40.08% vs. 1.94%, P?<?0.001), hair (29.25% vs. 13.29%, P?=?0.002) and nails (30.21% vs. 13.64%, P?=?0.003) than the healthy controls', indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P?=?0.047) and hepatic steatosis (0.19 vs. 0.3, P?=?0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI).ConclusionsThe long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.

Dataset Information

Role of Signal Regulatory Protein ? in Arsenic Trioxide-induced Promyelocytic Leukemia Cell Apoptosis.

Publications

Role of Signal Regulatory Protein α in Arsenic Trioxide-induced Promyelocytic Leukemia Cell Apoptosis.

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