背景:发现白血病干细胞(LSCs)是导致急性髓细胞性白血病(AML)疗效不佳的主要因素之一,因为它们受到骨髓微环境(BMM)的保护,可以抵抗常规疗法。醋酸棉酚(GAA),它是从棉花植物的种子中提取的,在几种类型的癌症中发挥抗肿瘤作用,并已报道通过抑制Bcl2诱导LSCs凋亡。
目的:探讨GAA在不同微环境下对LSCs的调控作用及其作用机制。
方法:在本研究中,从AML细胞系中磁性分选LSC,并获得CD34+CD38-群体。在LSCs中评估富含亮氨酸的五肽重复蛋白(LRPPRC)和叉头盒M1(FOXM1)的表达,并测量了GAA对恶性肿瘤和线粒体功能的影响。
结果:发现LRPPRC上调,GAA通过降解LRPPRC抑制细胞增殖。GAA诱导LRPPRC降解并抑制白细胞介素6(IL-6)/Janus激酶(JAK)1/信号转导和转录激活因子(STAT)3信号的激活,增强LSCs对常规化疗的化学敏感性,包括L-天冬酰胺酶,地塞米松,和阿糖胞苷.还发现GAA通过调节LRPPRC间接下调FOXM1。此外,GAA诱导活性氧积累,线粒体稳态紊乱,并导致线粒体功能障碍.通过降解LRPPRC抑制IL-6/JAK1/STAT3信号,GAA导致LSC的消除。同时,GAA通过引起线粒体损伤来诱导氧化应激和随后的细胞损伤。
结论:综合来看,结果表明GAA可能克服了BMM的保护作用,被认为是治疗AML的一种新型有效的联合治疗方法.
BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.
OBJECTIVE: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.
METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured.
RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.
CONCLUSIONS: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.