哈佛系主任《Nature》癌细胞“挟持”抗氧化剂

　　

生物通报道，哈佛大学医学院细胞生物学系，Dana-Farber癌症研究所，Johns Hopkins大学医学院细胞生物学系的科学家在最新一期的Nature杂志上发表癌细胞利用抗氧化剂的研究进展文章Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment。

 

文章通讯作者是哈佛大学细胞生物学系的现任主任Joan S. Brugge，早年曾在制药企业担任科学家职位。

 

抗氧化剂一直被认为是抵抗衰老，保护DNA完整性的活性成分，实验室研究和动物临床研究数据表明，抗氧化剂还具有抑制癌症发生的功能。尽管，抗氧化剂抑制癌症发生的论点还没有在人类临床试验上被证明，抗氧剂是有利健康的活性分子的论点是受认同的。

 

然而，Joan S. Brugge等人新的研究发现在某些条件下抗氧化剂能促进癌细胞存活和帮助癌细胞增殖。

 

正常表皮细胞如果与在结构上具有支持作用的细胞外基质脱离会引起代谢缺陷，然后死亡。然而，在乳腺癌中，促癌基因erbB2能为脱离的肿瘤发生细胞提供存活信号，帮助乳腺癌细胞脱离代谢缺陷。

 

与此同时，癌症发生时，抗氧化剂能通过经由脂肪酸氧化提升细胞能量水平来避免癌细胞陷入代谢缺陷，增强癌细胞在脱离基质环境中的存活能力。原本可阻止癌症发生的抗氧化剂被癌细胞挟持利用，归为己用。

 

这些发现指出了癌症发生时利用抗氧化剂的机制。

（生物通 小茜）

生物通推荐原文检索

Nature 461, 109-113 (3 September 2009) | doi:10.1038/nature08268; Received 13 March 2009; Accepted 6 July 2009; Published online 19 August 2009

 

Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment

Zachary T. Schafer1,4, Alexandra R. Grassian1,5, Loling Song1,5, Zhenyang Jiang1, Zachary Gerhart-Hines2,3, Hanna Y. Irie1, Sizhen Gao1, Pere Puigserver1,2 & Joan S. Brugge1

 

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Present address: Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA.

 

【Abstract】

Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence1. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment2, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells3, 4. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport. Overexpression of ERBB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and phosphatidylinositol-3-OH kinase (PI(3)K) activation, and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. Notably, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an increase in ROS in matrix-deprived cells in the luminal space of mammary acini, and the discovery that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results show both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments by antioxidant restoration of ATP generation.