转谷氨酰胺酶2通过mTOR通路和自噬调控全反式维甲酸诱导的白血病细胞HL60和U937的髓系分化

TGM2 Regulates All-Trans Retinoic Acid-Induced Myeloid Differentiation of Leukemia Cells HL60 and U937 Through the mTOR Pathway and Autophagy

全反式维甲酸(ATRA)是具有融合基因PML-RARα的急性早幼粒细胞白血病(APL)特异的靶向治疗药物。此外,ATRA在无PML-RARα融合的急性髓系白血病及其它一些肿瘤中也有一定治疗效果。但ATRA治疗也会引起一些并发症或发生愈后复发。因此,对ATRA诱导分化调控机制的研究非常重要。转谷氨酰胺酶2(TGM2)是一种多功能酶,能调控mTOR信号通路和自噬等。ATRA能诱导APL细胞中TGM2表达上调,TGM2敲低抑制ATRA诱导的细胞分化。但其调控机制及涉及的信号通路尚不明确。本研究发现,在HL60和U937细胞中,ATRA能够上调CD11b和TGM2的表达(P<0.05),抑制mTOR信号通路,并增强自噬;与对照相比,敲低TGM2,mTOR信号通路增强,自噬被抑制,而ATRA诱导的CD11b表达被抑制(P<0.05),分化减弱,被ATRA抑制的mTOR信号通路得到部分恢复,而被ATRA增强的自噬适当减弱。这表明ATRA使HL60和U937细胞发生髓系分化,并诱导TGM2表达升高;而TGM2通过mTOR信号通路和自噬途径调控ATRA诱导的髓系分化。该研究将有利于更深入地了解ATRA诱导白血病细胞分化的过程和机制,也有利于加深对TGM2的多功能性的认识;有助于对APL等白血病及其它癌症的药物诱导疗法的探讨。

All-trans retinoic acid(ATRA) is a targeted therapy drug for acute promyelocytic leukemia(APL) with the specific fusion gene promyelocytic leukemia(PML)-retinoic acid receptor α(RARα).In addition,ATRA also has a certain therapeutic effect in acute myeloid leukemia without PML-RARα and some other tumors.However,ATRA treatment can also cause some complications or recurrence after recovery.Therefore,it is very important to study the regulatory mechanism of ATRA-induced differentiation.Transglutaminase 2(TGM2) is a multifunctional enzyme that regulates the mammalian target of rapamycin(mTOR) signaling pathway and autophagy.ATRA can up-regulate the expression of TGM2 in APL cells,and TGM2 knockdown inhibits ATRA-induced cell differentiation.However,its regulatory mechanism and the signaling pathways involved are still unclear.This study found that in HL60 and U937 cells,ATRA could up-regulate the expression of CD11b and TGM2(P<0.05),inhibit the mTOR signaling pathway,and enhance autophagy.After knockdown of TGM2,the mTOR signaling pathway was enhanced and autophagy was inhibited,while ATRA-induced CD11b expression was inhibited(P<0.05).This indicates that ATRA induces myeloid differentiation in HL60 and U937 cells and induces increased expression of TGM2,and TGM2 regulates ATRA-induced myeloid differentiation through mTOR signaling pathway and autophagy.This study will help to better understand the process and mechanism of ATRA-induced leukemia cell differentiation,and deepen the understanding of the multifunctionality of TGM2,which will help to explore the drug-induced therapy for APL,other leukemias and other cancers.