Puigvert Jordi Carreras, Huveneers Stephan, Fredriksson Lisa, op het Veld Marieke, van de Water Bob, Danen Erik H J
Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Mol Pharmacol. 2009 Apr;75(4):947-55. doi: 10.1124/mol.108.051649. Epub 2009 Jan 21.
Chemotherapy often relies on cancer cell death resulting from DNA damage. The p53 tumor suppressor pathway that is an important player in DNA damage response is frequently inactivated in cancer. Genotoxicants also activate DNA damage-independent stress pathways and activity of oncogenic signaling and adhesive interactions with the cancer microenvironment can have a strong impact on chemosensitivity. Here, we have investigated how two different oncogenes modulate the response to genotoxicants in the context of two classes of integrin adhesion receptors. Epithelial cells expressing either beta1 or beta3 integrins, in which p53 activity is suppressed, undergo G(2) arrest but show little apoptosis after treatment with cisplatin or other genotoxicants. The apoptotic response is strongly enhanced by the c-Src[Y530F] oncogene in cells expressing beta1 integrins, whereas such sensitization is reduced when these cells are engineered to express beta3 integrins instead. The H-Ras[G12V] oncogene fails to sensitize, regardless of the integrin expression profile. The enhanced sensitivity induced by c-Src[Y530F] in the context of beta1 integrins does not rely on p53-mediated DNA damage signaling but instead involves increased endoplasmic reticulum stress and caspase-3 activation. Our data implicate that the expression profiles of oncogenes and integrins strongly affect the response to chemotherapeutics and may thus determine the efficacy of chemotherapy.
化疗通常依赖于由DNA损伤导致的癌细胞死亡。p53肿瘤抑制通路是DNA损伤反应中的重要参与者，在癌症中常常失活。基因毒性物质也会激活与DNA损伤无关的应激通路，致癌信号的活性以及与癌症微环境的黏附相互作用会对化学敏感性产生强烈影响。在此，我们研究了在两类整合素黏附受体的背景下，两种不同的癌基因如何调节对基因毒性物质的反应。表达β1或β3整合素且p53活性受到抑制的上皮细胞，在用顺铂或其他基因毒性物质处理后会发生G2期阻滞，但几乎不发生凋亡。在表达β1整合素的细胞中，c-Src[Y530F]癌基因可强烈增强凋亡反应，而当这些细胞被改造为表达β3整合素时，这种致敏作用则会减弱。无论整合素表达情况如何，H-Ras[G12V]癌基因均无法使细胞致敏。在β1整合素背景下，c-Src[Y530F]诱导的敏感性增强并不依赖于p53介导的DNA损伤信号传导，而是涉及内质网应激增加和半胱天冬酶-3激活。我们的数据表明，癌基因和整合素的表达谱强烈影响对化疗药物的反应，因此可能决定化疗的疗效。
