Sharma Sreenath V, Gajowniczek Patrycja, Way Inna P, Lee Diana Y, Jiang Jane, Yuza Yuki, Classon Marie, Haber Daniel A, Settleman Jeffrey
Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Cancer Cell. 2006 Nov;10(5):425-35. doi: 10.1016/j.ccr.2006.09.014.
"Oncogene addiction" describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of prosurvival and proapoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and -STAT3/5, and a delayed accumulation of the proapoptotic effector phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes and suggest that "addiction" associated with apoptosis reflects an active rather than a passive process.
“癌基因成瘾”描述了癌细胞在生存或增殖方面对特定细胞信号通路存在的一种无法解释的依赖性。我们报告称，癌基因依赖型细胞中促生存信号和促凋亡信号的不同衰减速率，导致癌基因失活后细胞死亡。Src、BCR-ABL和表皮生长因子（EGF）受体依赖型细胞在癌基因失活后表现出相似的信号衰减特征，其特点是磷酸化细胞外信号调节激酶（ERK）、蛋白激酶B（Akt）和信号转导子和转录激活子3/5（STAT3/5）迅速减少，而促凋亡效应分子磷酸化p38丝裂原活化蛋白激酶（p38 MAPK）延迟积累。这些发现表明，在对癌基因失活的凋亡反应中，生存和凋亡致癌输出存在短暂失衡。此外，这些观察结果表明多种癌基因存在共同的信号衰减特征，并提示与凋亡相关的“成瘾”反映的是一个主动而非被动的过程。
