Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism.
Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism.
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DOI：
10.1158/0008-5472.can-10-3397
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发表时间：
2011-10-15
期刊：
影响因子：
11.2
通讯作者：
Fisher RA
中科院分区：
文献类型：
--
作者：
Huang J;Yang J;Maity B;Mayuzumi D;Fisher RA
多柔比星（DXR）是最广泛使用的癌症化疗药物之一，它通过激活ATM并由此上调肿瘤抑制因子p53来促进癌细胞死亡。DXR激活ATM的确切机制尚不完全清楚。本研究发现了G蛋白信号6调节剂（RGS6）在介导DXR激活ATM和p53中的新作用。RGS6被DXR强烈诱导，RGS6基因缺失显著损害了DXR诱导的ATM和p53的激活及其在心脏中的凋亡作用。RGS6促进p53激活以响应DXR的能力与RGS6与G蛋白的相互作用无关，但需要ATM。RGS6通过ros依赖和DNA损伤无关的机制介导DXR对ATM和p53的激活。这一机制代表了DXR促进atm -p53-凋亡通路激活的主要手段，这是其细胞毒性活性的基础。我们的研究结果与经典理论相矛盾，这些理论认为DXR主要通过直接或间接（通过ROS）促进DNA损伤来激活ATM， RGS6的功能是通过与G蛋白的相互作用介导的。这些发现揭示了DXR化疗作用的新机制，并确定了RGS6作为癌症化疗的新靶点。
Doxorubicin (DXR), among the most widely used cancer chemotherapy agents, promotes cancer cell death via activation of ATM and the resultant up-regulation of tumor suppressor p53. The exact mechanism by which DXR activates ATM is not fully understood. Here we discovered a novel role for Regulator of G protein Signaling 6 (RGS6) in mediating activation of ATM and p53 by DXR. RGS6 was robustly induced by DXR, and genetic loss of RGS6 dramatically impaired DXR-induced activation of ATM and p53, as well as its in vivo apoptotic actions in heart. The ability of RGS6 to promote p53 activation in response to DXR was independent of RGS6 interaction with G proteins but required ATM. RGS6 mediated activation of ATM and p53 by DXR via a ROS-dependent and DNA damage-independent mechanism. This mechanism represents the primary means by which DXR promotes activation of the ATM-p53-apoptosis pathway that underlies its cytotoxic activity. Our findings contradict the canonical theories that DXR activates ATM primarily by promoting DNA damage either directly or indirectly (via ROS) and that RGS6 function is mediated by its interactions with G proteins. These findings reveal a new mechanism for the chemotherapeutic actions of DXR and identify RGS6 as a novel target for cancer chemotherapy.