Sphingolipids: key regulators of apoptosis and pivotal players in cancer drug resistance.
Sphingolipids: key regulators of apoptosis and pivotal players in cancer drug resistance.
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DOI：
10.3390/ijms15034356
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发表时间：
2014-03-12
影响因子：
5.6
通讯作者：
Venerando B
中科院分区：
文献类型：
--
作者：
Giussani P;Tringali C;Riboni L;Viani P;Venerando B
癌细胞引起的耐药性仍然是一个巨大的问题，经常损害传统和新型分子疗法的功效。化疗通常会诱导癌细胞凋亡；因此，对细胞凋亡控制和癌细胞逃避细胞凋亡的机制的研究可以转化为治疗方法的改进。在癌细胞为此获得的许多工具中，鞘脂的合成和代谢失调已被充分记录。鞘脂已知在细胞中发挥许多结构和信号传导作用，因为它们参与生长、存活、粘附和运动的控制。具体而言，为了增加存活率，癌细胞： (a) 抵消具有促凋亡潜力并由许多药物诱导的神经酰胺的积累； (b) 增加作为促生存信号的1-磷酸鞘氨醇和葡萄糖神经酰胺的合成； (c) 改变复杂鞘糖脂的合成和代谢，特别是增加神经节苷脂的修饰种类的水平，例如 9-O 乙酰化 GD3 (αNeu5Ac(2-8)αNeu5Ac(2-3)βGal(1-4)βGlc(1-1)Cer) 或 N-乙醇酰基 GM3 (αNeu5Ac) (2-3)βGal(1-4)βGlc(1-1)Cer) 和 de-N-乙酰基 GM3 (NeuNH(2)βGal(1-4)βGlc(1-1)Cer) 具有抗凋亡作用，而球苷 Gb3 则与多药耐药基因 MDR1 的较高表达有关。鉴于这一证据，采用专门针对鞘脂失调的化学或遗传方法似乎是提高当前化疗疗效的有前途的工具。
Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a) counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b) increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c) modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (αNeu5Ac(2-8)αNeu5Ac(2-3)βGal(1-4)βGlc(1-1)Cer) or N-glycolyl GM3 (αNeu5Ac (2-3)βGal(1-4)βGlc(1-1)Cer) and de-N-acetyl GM3 (NeuNH(2)βGal(1-4)βGlc(1-1)Cer) endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy.
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DOI：
10.1073/pnas.1115484108
发表时间：
2011-12-06
影响因子：
11.1
作者：
Barcelo-Coblijn, Gwendolyn;Laura Martin, Maria;Escriba, Pablo V.
通讯作者：
Escriba, Pablo V.
影响因子：
4.8
作者：
Chalfant, CE;Ogretmen, B;Hannun, YA
通讯作者：
Hannun, YA
DOI：
10.5402/2011/645641
发表时间：
2011
期刊：
ISRN gastroenterology
影响因子：
--
作者：
Blanco R;Rengifo E;Cedeño M;Rengifo CE;Alonso DF;Carr A
通讯作者：
Carr A
影响因子：
3.9
作者：
Birklé, S;Zeng, G;Aubry, J
通讯作者：
Aubry, J
影响因子：
4.8
作者：
Adams, DG;Coffee, RL;Wadzinski, BE
通讯作者：
Wadzinski, BE