Department of Pediatrics, Children Hematological Oncology and Birth Defects Laboratory, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou, 646000, Sichuan, P. R. China.
CAS Key Laboratory of Environmental and Applied Microbiology, Environmental Microbiology Key Laboratory of Sichuan Province, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, Sichuan, P. R. China.
Chem Biodivers. 2022 Sep;19(9):e202200447. doi: 10.1002/cbdv.202200447. Epub 2022 Aug 24.
Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca levels, which resulted in calcium overload in T-ALL cells. Furthermore, on the basis of bioinformatics analyses, we focused on an osmotically regulated transcription factor, NFAT5. Molecular docking preliminarily indicated that PSPA molecules bound and interacted with the NFAT5 protein. Western blot analyses confirmed that PSPAs elicited calcium overload by nonosmotic regulation of NFAT5/S100A4-S100A9 pathway activation. Moreover, pretreatment with a NFAT5 inducer confirmed that PSPAs targeted NFAT5 and affected p38/NF-κB/Bcl-2/Caspase-3 axis activation. This study demonstrates that PSPAs exert their antileukemic effects through calcicoptosis induction by targeting NFAT5.
紫薯被认为是一种丰富、廉价且理想的花色苷来源。由于酰化花色苷的丰富，紫薯花色苷（PSPA）已被证明具有高抗突变性和抗肿瘤作用。然而，PSPA 对急性淋巴细胞白血病（ALL），特别是 T 细胞急性淋巴细胞白血病（T-ALL）的影响及其潜在机制尚不清楚。在这项研究中，通过体外和计算机模拟试验评估了 PSPA 的抗白血病作用及其潜在的分子机制。分析和定量了十种品种的 PSPA。选择 Nanzi 018 中的花色苷进行分析，因其具有最佳的抗白血病作用。首先，PSPA 强烈降低了细胞活力并诱导了细胞凋亡。此外，PSPA 急剧增加了细胞内 Ca 水平，导致 T-ALL 细胞中钙超载。此外，基于生物信息学分析，我们专注于一种渗透调节转录因子 NFAT5。分子对接初步表明 PSPA 分子与 NFAT5 蛋白结合并相互作用。Western blot 分析证实 PSPA 通过非渗透调节 NFAT5/S100A4-S100A9 通路激活引起钙超载。此外，用 NFAT5 诱导剂预处理证实 PSPA 靶向 NFAT5 并影响 p38/NF-κB/Bcl-2/Caspase-3 轴的激活。本研究表明，PSPA 通过靶向 NFAT5 诱导钙性细胞凋亡发挥其抗白血病作用。
