5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）对三阴性乳腺癌（TNBC）细胞的抗癌作用：作为潜在机制的线粒体调节。
Anti-cancer Effects of 5-Aminoimidazole-4-Carboxamide-1-β-D-Ribofuranoside (AICAR) on Triple-negative Breast Cancer (TNBC) Cells: Mitochondrial Modulation as an Underlying Mechanism.
机构信息
School of Biotechnology, Devi Ahilya University, Indore-452001. M.P., India.
Laboratory of Membrane Protein Biology, National Centre for Cell Science, NCCS Complex, S. P. Pune University, Pune, Maharashtra 411007, India.
出版信息
Curr Cancer Drug Targets. 2022;22(3):245-256. doi: 10.2174/1568009622666220207101212.
BACKGROUND
Triple-negative breast cancer (TNBC) is known for Warburg effect and defects in the mitochondria. AMP-dependent kinase (AMPK) activates the downstream transcription factors PGC-1α, PGC-1β, or FOXO1, which participate in mitochondrial biogenesis. 5- aminoimidazole-4-carboxamide riboside (AICAR) is an analog of adenosine monophosphate and is a direct activator of AMPK.
OBJECTIVES
In the present study, we have made an attempt to understand the influence of AICAR on TNBC cells, MDA-MB-231, and the underlying changes in mitochondrial biogenesis, if any.
METHODS
We investigated AICAR induced changes in cell viability, apoptosis, migratory potential, and changes in the sensitivity of doxorubicin.
RESULTS
In response to the treatment of MDA-MB-231 breast cancer cells with 750 μM of AICAR for 72 hours, followed by 48 hours in fresh media without AICAR, we observed a decrease in viability via MTT assay, reduction in cell numbers along with the apoptotic appearance, increased cell death by ELISA, decreased lactate in conditioned medium and decrease in migration by scratch and transwell migration assays. These changes in the cancer phenotype were accompanied by an increase in mitochondrial biogenesis, as observed by increased mitochondrial DNA to nuclear DNA ratio, a decrease in lactic acid concentration, an increase in MitoTracker green and red staining, and increased expression of transcription factors PGC-1α, NRF-1, NRF-2, and TFAM, contributing to mitochondrial biogenesis. Pre-treatment of cells with AICAR for 72 hours followed by 48 hours treatment with 1 μM doxorubicin showed an increased sensitivity to doxorubicin as assessed by the MTT assay.
CONCLUSION
Our results show that AICAR exerts beneficial effects on TNBC cells, possibly via switching off the Warburg effect and switching on the anti-Warburg effect through mitochondrial modulation.
背景
三阴性乳腺癌（TNBC）以瓦博格效应和线粒体缺陷为特征。AMP 依赖性激酶（AMPK）激活下游转录因子 PGC-1α、PGC-1β 或 FOXO1，参与线粒体生物发生。5-氨基咪唑-4-甲酰胺核苷（AICAR）是腺苷一磷酸的类似物，是 AMPK 的直接激活剂。
目的
本研究试图了解 AICAR 对 TNBC 细胞 MDA-MB-231 的影响，以及是否存在线粒体生物发生的潜在变化。
方法
我们研究了 AICAR 诱导的细胞活力、凋亡、迁移潜力变化以及阿霉素敏感性变化。
结果
用 750μM AICAR 处理 MDA-MB-231 乳腺癌细胞 72 小时，然后在不含 AICAR 的新鲜培养基中培养 48 小时，通过 MTT 分析观察到细胞活力下降，细胞数量减少，出现凋亡形态，ELISA 检测到细胞死亡增加，条件培养基中乳酸减少，划痕和 Transwell 迁移试验中迁移减少。这些癌症表型的变化伴随着线粒体生物发生的增加，表现为线粒体 DNA 与核 DNA 比值增加、乳酸浓度降低、MitoTracker 绿色和红色染色增加以及转录因子 PGC-1α、NRF-1、NRF-2 和 TFAM 的表达增加，促进线粒体生物发生。用 AICAR 预处理细胞 72 小时，然后用 1μM 阿霉素处理 48 小时，通过 MTT 分析显示对阿霉素的敏感性增加。
结论
我们的结果表明，AICAR 对 TNBC 细胞具有有益作用，可能通过调节线粒体来关闭瓦博格效应并开启抗瓦博格效应。
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