Chen Xi, Song Yan, Tian Yaoyao, Dong Xiushuai, Chang Yuying, Wang Wei
Department of Hemotology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Cell Biochem Biophys. 2024 Dec;82(4):3287-3296. doi: 10.1007/s12013-024-01412-8. Epub 2024 Aug 17.
Acute myeloid leukemia (AML) is a kind of heterogeneous hematologic malignancy with high incidence, which is usually treated by intensive and maintenance treatment with large dose of conventional chemotherapy drugs. However, cell resistance is still an unsolved problem. The abnormal expression of miRNAs is closely related to the pathogenesis and progression of AML, and affects the drug resistance of cancer cells. miR-149-3p plays an important role in the resistance of cancer cells to cisplatin, and plays an excellent anti-tumor activity. By studying the function of miR-149-3p, it is expected to find new therapeutic methods to reverse chemotherapy resistance. In order to explore the mechanism of action of miR-149-3p on AML chemotherapeutic drug sensitivity, we explored the relationship between the Warburg effect and AML chemotherapeutic drug resistance. Based on AML cells, transfection of miR-149-3p inhibitor/NC and Warburg effect inhibitor (2DG) and PI3K/AKT pathway inhibitor (LY294002) were used to investigate the mechanism of IFN-γ regulating chemotherapy resistance of AML cells through Warburg effect. Down-regulation of miR-149-3p significantly inhibited drug sensitivity of AML cells. Down-regulation of miR-149-3p significantly promoted proliferation and invasion of AML cells while inhibiting apoptosis by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. Down-regulation of miR-149-3p significantly promoted the expression of Warburg effect-related proteins hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and Glucose transporter 1 (GLUT1), glucose consumption, lactic acid, and intracellular ATP production. After inhibiting the Warburg effect with 2DG, the effect of miR-149-3p was inhibited, suggesting that upregulation of miR-149-3p reversed AML cell resistance by inhibiting the Warburg effect. In addition, miR-149-3p interacted with AKT1. Down-regulation of miR-149-3p increased the expression of inosine phosphate 3 kinase (PI3K), protein kinase B (AKT), and multi-drug resistance protein (MDR1). LY294002 inhibited the expression of these proteins, and down-regulation of miR-149-3p reversed the effect of LY294002 and improved the drug resistance of cells. Upregulation of miR-149-3p expression may potentially be a therapeutic target for AML resistance. It has been shown to inhibit PI3K/AKT pathway activation, thereby inhibiting the Warburg effect, and affecting cell proliferation, apoptosis, and drug resistance.
急性髓系白血病（AML）是一种发病率较高的异质性血液系统恶性肿瘤，通常采用大剂量传统化疗药物进行强化和维持治疗。然而，细胞耐药性仍是一个尚未解决的问题。微小RNA（miRNA）的异常表达与AML的发病机制和进展密切相关，并影响癌细胞的耐药性。miR-149-3p在癌细胞对顺铂的耐药中起重要作用，并具有出色的抗肿瘤活性。通过研究miR-149-3p的功能，有望找到逆转化疗耐药性的新治疗方法。为了探究miR-149-3p对AML化疗药物敏感性的作用机制，我们探讨了瓦伯格效应与AML化疗药物耐药性之间的关系。以AML细胞为基础，转染miR-149-3p抑制剂/阴性对照（NC）以及瓦伯格效应抑制剂（2-脱氧-D-葡萄糖，2DG）和磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（AKT）通路抑制剂（LY294002），以研究干扰素-γ（IFN-γ）通过瓦伯格效应调节AML细胞化疗耐药性的机制。miR-149-3p的下调显著抑制了AML细胞的药物敏感性。miR-149-3p的下调通过上调Bcl-2的表达和下调Bax的表达，显著促进了AML细胞的增殖和侵袭，同时抑制了细胞凋亡。miR-149-3p的下调显著促进了瓦伯格效应相关蛋白己糖激酶2（HK2）、乳酸脱氢酶A（LDHA）和葡萄糖转运蛋白1（GLUT1）的表达、葡萄糖消耗、乳酸生成以及细胞内三磷酸腺苷（ATP）的产生。用2DG抑制瓦伯格效应后，miR-149-3p的作用受到抑制，这表明上调miR-149-3p通过抑制瓦伯格效应逆转了AML细胞的耐药性。此外，miR-149-3p与AKT1相互作用。miR-149-3p的下调增加了磷酸肌醇3激酶（PI3K）、蛋白激酶B（AKT）和多药耐药蛋白（MDR1）的表达。LY294002抑制了这些蛋白的表达，而miR-149-3p的下调逆转了LY294002的作用并提高了细胞的耐药性。上调miR-149-3p的表达可能是AML耐药的一个治疗靶点。已表明它可抑制PI3K/AKT通路的激活，从而抑制瓦伯格效应，并影响细胞增殖、凋亡和耐药性。
