Cancer Cell特刊文章 癌症终极弱点

　　

生物通报道，伊利诺大学芝加哥校区生物化学与分子遗传学院，医学院，Jesse Brown VA医学研究中心的科学家在12月9日出版的Cancer Cell上发表特刊文章，讲述氧化作用路径与细胞衰老以及细胞凋亡间的关联。

 

文章通讯作者Nissim Hay博士早年在以色列Weizmann研究所获得博士学位，现在利诺大学芝加哥校区生物化学与分子遗传学院任教授，主要研究细胞分裂，细胞代谢和癌症的遗传学变化，主要应用的技术包括，细胞生物学技术，生物化学技术，分子生物学技术和基因敲除技术。

 

Akt通路是膜受体信号向细胞内转导的重要途径，它们调节着细胞凋亡、生长以及一些重要基因的表达。

 

Akt缺陷会导致对衰老性复制产生耐受作用，对氧化应激或致癌基因Ras诱导的早衰产生耐受作用，同时还对活性氧簇（reactive oxygen species，ROS）介导的细胞凋亡产生耐受作用。

 

Akt活化可诱导早衰，并通过增加胞内ROS增加氧耗量和表达ROS清除下游FoxO尤其是sestrin3致敏ROSE介导的细胞凋亡作用。这些结果表明，研究者找到Ark的关键弱点，可以逆转Akt通过多种细胞凋亡刺激因子诱导细胞凋亡的过程。Akt可以停止抑制ROS介导的细胞凋亡。

 

研究小组还发现，用rapamycin治疗癌症可促进激活Ak，抑制etopototic超敏化，促进癌细胞凋亡。单独使用rapamycin可有选择性地激活Akt清除癌细胞。

生物通 张欢

Nissim Hay代表文章

 

Skeen, J. E., Bhaskar, P. T., Chen, C. C., Chen, W. S., Peng, X. D., Nogueira, V., Hahn-Windgassen, A., Kiyokawa, H., and Hay, N. (2006). Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell 10, 269-280.

 

Chen, M. L., Xu, P. Z., Peng, X., Chen, W. S., Guzman, G., Yang, X., Di Cristofano, A., Pandolfi, P. P., and Hay, N. (2006). The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes Dev 20, 1569-1574.

 

Robey, R. B., and Hay, N. (2006). Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25, 4683-4696.

 

Hahn-Windgassen, A., Nogueira, V., Chen, C. C., Skeen, J. E., Sonenberg, N., and Hay, N. (2005). Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280, 32081-32089.

 

Hay, N. (2005). The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8, 179-183.

 

Robey, R. B., and Hay, N. (2005). Akt, hexokinase, mTOR: Targeting cellular energy metabolism for cancer therapy. Drug Discovery Today, in press.

 

Robey, R. B., and Hay, N. (2005). Mitochondrial hexokinases: guardians of the mitochondria. Cell Cycle 4, 654-658.

 

 

Majewski N., Nogueira V., Bhaskar P., Coy P. E., Skeen J.E, Gottlob, K., Chandel N. S., Thompson C. B, Robey R. B, and Hay, N. 2004. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16: 819-830.

 

Hay N, Sonenberg N. 2004. Upstream and downstream of mTOR. Genes Dev. 18: 1926- 1945.

 

Majewski, N., V. Nogueira, R. B. Robey, and N. Hay. 2004. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Molec. Cell. Biol. 24:730-740.

 

Peng, X. D., P. Z. Xu, M. L. Chen, A. Hahn-Windgassen, J. Skeen, J. Jacobs, D. Sundararajan, W. S. Chen, S. E. Crawford, K. G. Coleman, and N. Hay. 2003. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1

and Akt2. Genes Dev 17:1352-65.

 

Kandel, E. S., Skeen J., Majewski, N., Di Cristofano, A., Pandolfi, P.P, Feliciano CS, Gartel A, and Hay, N. (2002). Activation of Akt/PKB overcomes G2/M cell cycle checkpoint following DNA damage. Molec, Cell. Biol. 22: 7831- 7841.

 

Chen, W., Xu, P-Z., Gottlob, K., Chen, M-L., Sokol, K., Shiyanova, T., Roninson, I., Weng, W., Suzuki, R., Tobe, K., Kadowaki, T., and Hay, N. (2001). Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene. Genes and Development 15: 2203-2208.

 

Gottlob, K., Majewski, N., Kennedy, S., Kandel, E., Robey, R.B., and Hay, N. (2001). Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes and Development 15: 1406-1418.

 

Wert, M., Kennedy, S., Palfrey, H.C., and Hay, N. (2001) Myc drives apoptosis in PC12 cells in the absence of Max. Oncogene 20: 3746-3750.

 

Kokontis, J.M., Wagner, A.J., Liao, S., and Hay, N. (2001) The transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function. Oncogene 20: 659-668.

 

Conzen, S.D., Gottlob, K., Kandel, E.S., Khanduri, P., Wagner, A.J., O’Leary, M., and Hay, N. (2000) Induction of Cell Cycle Progression and Acceleration of Apoptosis Are Two Separable Functions of c-Myc: Transrepression Correlates with Acceleration of Apoptosis. Molec. Cell. Biol. 20: 6008-18

 

Kandel, E.S., and Hay, N. (1999). Multiple regulators and multiple downstream effectors of the serine/threonine kinase Akt/PKB. Experimental Cell Res. 253: 210-229.

 

Kennedy, S.G., Kandel, E.S., Cross, T.K., and Hay, N. (1999). Akt/PKB inhibits cell death by preventing the release of cytochrome c from mitochondria. Molec. Cell. Biol. 19: 5800-5810.

 

Gingras, A.-C., Kennedy, S.G., O’Leary, M., Sonenberg, N., and Hay, N. (1998). The repressor of mRNA translation, 4E-BP1, is phosphorylated and inactivated by Akt(PKB)-dependent signaling pathway. Genes and Development 12: 502-513.

 

Kennedy, S., Wagner, A.J., Conzen S.D., Jordan, J., Bellacosa, A., Tsichlis, P.N., and Hay, N. (1997). PI 3-kinase/Akt(PKB) signaling pathway delivers an anti-apoptotic signal. Genes and Development 11: 701-713.

 

Wagner, A.J., Kokontis, J., and Hay, N. (1994) Myc-mediated apoptosis requires wild type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes and Development 8: 2817-2830.

 

Wagner, A.J., Small, M.B., and Hay, N. (1993) Myc mediated apoptosis is blocked by ectopic expression of Bcl2. Molec. Cell. Biol. 13: 2432-2440.

 

DesJardins, E. and Hay, N. (1993) Repeated CT-elements bound by zinc finger proteins control the absolute and relative activities of the two principal human c-myc promoters. Molec. Cell. Biol. 13: 5710-5724.

 

Wagner, A.J., Meyers, C., Laimins, L., and Hay, N. (1993). c-Myc induces ornithine decarboxylase expression and activity. Cell Growth & Differentiation 4: 879-883.

 

 

Amin, C., Wagner, A.J., and Hay, N. (1993) Sequence-specific transcriptional activation by Myc and repression by Max. Molec. Cell. Biol. 13: 383-390.