Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana.
Mol Carcinog. 2014 May;53(5):403-12. doi: 10.1002/mc.21988. Epub 2012 Dec 19.
Chemoprevention has been a pivotal and effective strategy during the skin cancer treatment. Using human skin normal and tumor samples, we demonstrated that both the expression and activity levels of pyruvate kinase M2 (PKM2) were higher in skin tumor tissues than normal tissues, suggesting that PKM2, one of important metabolic enzyme, might serve as a target for skin cancer prevention and/or therapy. Shikonin, a small-molecule active chemical, has been studied as an anti-cancer drug candidate in human cancer models. However, the mechanism of action and the chemopreventive potential of shikonin are unclear. Herein, we used the skin epidermal JB6 P+ cells and demonstrated that shikonin suppressed the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) induced neoplastic cell transformation and PKM2 activation in the early stage of carcinogenesis. Mitochondrial functions were inhibited by TPA treatment, as indicated by reduced mitochondrial membrane potential and mitochondrial respiration, which were restored by shikonin. We also examined the levels of lactate as a glycolysis marker, and shikonin suppressed its increase caused by tumor promoter treatment. Modulation of cell metabolism by shikonin was associated with G2-M phase accumulation, and Fra-1 (a major subunit of activator protein 1 in skin tumorigenesis) downregulation. In addition, we demonstrated that AMP-activated protein kinase (AMPK), an energy sensor, which is inactivated by TPA, shikonin could reverse AMPK activity. These results suggest that shikonin bears chemopreventive potential for human skin cancers in which PKM2 is upregulated, which might be mediated by inhibiting oncogenic activation, PKM2 activation, and mitochondrial dysfunction.
化学预防一直是皮肤癌治疗中的一个关键且有效的策略。使用人皮肤正常和肿瘤样本，我们证明了丙酮酸激酶 M2（PKM2）的表达和活性水平在皮肤肿瘤组织中均高于正常组织，这表明 PKM2 作为一种重要的代谢酶，可能作为皮肤癌预防和/或治疗的靶点。紫草素是一种小分子活性化学物质，已在人类癌症模型中被研究作为一种抗癌药物候选物。然而，紫草素的作用机制和化学预防潜力尚不清楚。在此，我们使用皮肤表皮 JB6 P+细胞，并证明紫草素抑制肿瘤促进剂 12-O-十四烷酰佛波醇 13-乙酸酯（TPA）诱导的早期致癌作用中的肿瘤细胞转化和 PKM2 激活。TPA 处理抑制了线粒体功能，表现为线粒体膜电位和线粒体呼吸降低，而紫草素可使其恢复。我们还检查了乳酸作为糖酵解标志物的水平，并且紫草素抑制了肿瘤促进剂处理引起的其增加。紫草素对细胞代谢的调节与 G2-M 期积累有关，并且 Fra-1（皮肤肿瘤发生中的激活蛋白 1 的主要亚基）下调。此外，我们证明了 AMP 激活的蛋白激酶（AMPK），一种能量传感器，被 TPA 失活，紫草素可以逆转 AMPK 活性。这些结果表明，紫草素具有化学预防人类皮肤癌的潜力，其中 PKM2 上调，这可能是通过抑制致癌激活、PKM2 激活和线粒体功能障碍来介导的。
