Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPKα1/2-LKB1.
Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPKα1/2-LKB1.
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DOI：
10.1038/s41598-017-01659-7
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发表时间：
2017-05-04
影响因子：
4.6
通讯作者：
Katiyar SK
中科院分区：
文献类型：
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作者：
Pal HC;Prasad R;Katiyar SK
线粒体动力学和生物发生失调与包括癌症在内的各种病理状况有关。在这里，我们评估的治疗效果cryptolepine，一种生物碱的根Cryptolepis sanguinolenta，黑色素瘤细胞生长。用1.0、2.5、5.0和7.5 μM的Cryptolepine处理人黑色素瘤细胞系（A375、Hs 294 t、SK-Mel 28和SK-Mel 119）24和48 h，可显著抑制黑色素瘤细胞的生长（P < 0.001），但对正常黑素细胞无明显抑制作用。Cryptolepine的抑制作用与线粒体膜电位的丧失和Mfn 1、Mfn 2、Opa 1和p-Drp 1蛋白表达的降低相关，从而导致线粒体动力学的破坏。ATP水平和线粒体质量的降低与代谢肿瘤抑制因子AMPKα1/2-LKB 1的激活和mTOR信号转导的减少相关。SDH-A和COX-Ⅰ表达的降低表明Cryptolepine处理减少了线粒体生物合成。用Cryptolepine（10 mg/Kg体重，i. p.）导致肿瘤生长的显著抑制，这与线粒体动力学的破坏和线粒体生物发生的减少有关。我们的研究表明，低毒性的植物化学物质，如cryptolepine可以测试黑色素瘤的治疗。
Dysregulated mitochondrial dynamics and biogenesis have been associated with various pathological conditions including cancers. Here, we assessed the therapeutic effect of cryptolepine, a pharmacologically active alkaloid derived from the roots of Cryptolepis sanguinolenta, on melanoma cell growth. Treatment of human melanoma cell lines (A375, Hs294t, SK-Mel28 and SK-Mel119) with cryptolepine (1.0, 2.5, 5.0 and 7.5 μM) for 24 and 48 h significantly (P < 0.001) inhibited the growth of melanoma cells but not normal melanocytes. The inhibitory effect of cryptolepine was associated with loss of mitochondrial membrane potential and reduced protein expression of Mfn1, Mfn2, Opa1 and p-Drp1 leading to disruption of mitochondrial dynamics. A decrease in the levels of ATP and mitochondrial mass were associated with activation of the metabolic tumor suppressor AMPKα1/2-LKB1, and a reduction in mTOR signaling. Decreased expression of SDH-A and COX-I demonstrated that cryptolepine treatment reduced mitochondrial biogenesis. In vivo treatment of A375 xenograft-bearing nude mice with cryptolepine (10 mg/Kg body weight, i.p.) resulted in significant inhibition of tumor growth, which was associated with disruption of mitochondrial dynamics and a reduction in mitochondrial biogenesis. Our study suggests that low toxicity phytochemicals like cryptolepine may be tested for the treatment of melanoma.