Tanshinone IIA inhibits oral squamous cell carcinoma via reducing Akt-c-Myc signaling-mediated aerobic glycolysis
Tanshinone IIA inhibits oral squamous cell carcinoma via reducing Akt-c-Myc signaling-mediated aerobic glycolysis
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丹参酮 IIA 通过减少 Akt-c-Myc 信号介导的有氧糖酵解抑制口腔鳞状细胞癌
DOI：
10.1038/s41419-020-2579-9
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发表时间：
2020-05-18
影响因子：
9
通讯作者：
Li, Wei
中科院分区：
文献类型：
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作者：
Li, Ming;Gao, Feng;Li, Wei
有氧糖酵解是人类癌细胞的标志之一。己糖激酶2（HK 2）的过表达在维持肿瘤细胞无限生长中起着至关重要的作用。在本研究中，我们发现口腔鳞状细胞癌（OSCC）细胞表现出有氧糖酵解表型。此外，HK 2在OSCC患者来源的组织和细胞系中高度表达。在体外和体内，HK 2的耗尽抑制OSCC细胞的生长。通过天然产物筛选，我们确定丹参酮IIA（Tan IIA）是一种潜在的抗肿瘤化合物，通过抑制HK 2介导的糖酵解。Tan IIA可降低OSCC细胞的葡萄糖消耗和乳酸产生，并促进细胞凋亡。机制研究表明，Tan IIA抑制Akt-c-Myc信号通路，促进E3连接酶FBW 7介导的c-Myc泛素化和降解，最终在转录水平上降低HK 2的表达。总之，这些结果表明，靶向HK 2介导的有氧糖酵解是一种有前途的抗肿瘤策略，用于OSCC治疗。
Aerobic glycolysis is one of the hallmarks of human cancer cells. Overexpression of hexokinase 2 (HK2) plays a crucial role in the maintaining of unlimited tumor cell growth. In the present study, we found that the oral squamous cell carcinoma (OSCC) cells exhibited an aerobic glycolysis phenotype. Moreover, HK2 is highly expressed in OSCC patient derived-tissues and cell lines. Depletion of HK2 inhibited OSCC cell growth in vitro and in vivo. With a natural product screening, we identified Tanshinone IIA (Tan IIA) as a potential anti-tumor compound for OSCC through suppressing HK2-mediated glycolysis. Tan IIA decreased glucose consumption, lactate production, and promoted intrinsic apoptosis in OSCC cells. The mechanism study revealed that Tan IIA inhibited the Akt-c-Myc signaling and promoted E3 ligase FBW7-mediated c-Myc ubiquitination and degradation, which eventually reduced HK2 expression at the transcriptional level. In summary, these results indicate that targeting HK2-mediated aerobic glycolysis is a promising anti-tumor strategy for OSCC treatment.