Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species.
Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species.
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DOI：
10.1074/jbc.m110.200675
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发表时间：
2011-10-28
期刊：
影响因子：
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通讯作者：
Pillai MR
中科院分区：
文献类型：
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作者：
Achuthan S;Santhoshkumar TR;Prabhakar J;Nair SA;Pillai MR
背景：肿瘤干细胞参与肿瘤化疗后复发。结果：通过Nrf2-p21信号通路重新激活抗氧化酶有助于干细胞的浓缩。结论：NRF2通过降低26个S蛋白酶体活性稳定产生具有肿瘤干细胞样特性的细胞。意义：NRF2、26 S蛋白酶体和p21是化疗后出现耐药肿瘤干细胞的关键分子。化疗或放疗后肿瘤复发仍然是癌症治疗成功的主要障碍。癌细胞的一个子集，称为癌症干细胞，可以逃避常规治疗，最终再生出更具侵袭性的肿瘤。尽管有大量的研究，但控制化疗后出现具有干细胞特性的侵袭性治疗耐药细胞的分子事件尚不清楚。本研究为肿瘤细胞罕见地逃脱药物诱导的细胞死亡提供了证据，在经历了一段中间的非周期衰老阶段后，随后以自发细胞死亡为特征的不稳定增殖。然而，一些细胞似乎逃脱并产生稳定的克隆，具有侵袭性的肿瘤干细胞样表型。CD133和OCT-4高表达。值得注意的是，含有低水平活性氧簇(ROS)的药物选择细胞也显示出抗氧化酶的增加。与体外实验数据一致，我们观察到，与未接受术前化疗的样本相比，新辅助化疗后获得的乳腺肿瘤中的ROS水平较低。这些组织还表达了增强的ROS防御水平，并增强了超氧化物歧化酶的表达。在新辅助化疗后获得的肿瘤中也观察到较高的Oct-4和CD133水平。进一步的研究为NRF2的稳定性提供了证据，这是由于26 S蛋白酶体活性降低和p21结合增加作为驱动信号事件，促进了药物诱导的肿瘤干细胞从高ROS静止期向低ROS增殖期的转变。
Background: Tumor stem cells contribute to tumor recurrence after chemotherapy. Results: Reactivation of antioxidant enzymes through Nrf2-p21 signaling contributes to stem cell enrichment. Conclusion: Nrf2 stabilization through reduced 26 S proteasome activity generates cells with tumor stem cell-like properties. Significance: Nrf2, 26 S proteasome, and p21 are the key players in the emergence of drug-resistant tumor stem cells after chemotherapy. Tumor recurrence after chemotherapy or radiation remains a major obstacle to successful cancer treatment. A subset of cancer cells, termed cancer stem cells, can elude conventional treatments and eventually regenerate a tumor that is more aggressive. Despite the large number of studies, molecular events that govern the emergence of aggressive therapy-resistant cells with stem cell properties after chemotherapy are poorly defined. The present study provides evidence for the rare escape of tumor cells from drug-induced cell death, after an intermediate stay in a non-cycling senescent stage followed by unstable multiplication characterized by spontaneous cell death. However, some cells appear to escape and generate stable colonies with an aggressive tumor stem cell-like phenotype. These cells displayed higher CD133 and Oct-4 expression. Notably, the drug-selected cells that contained low levels of reactive oxygen species (ROS) also showed an increase in antioxidant enzymes. Consistent with this in vitro experimental data, we observed lower levels of ROS in breast tumors obtained after neoadjuvant chemotherapy compared with samples that did not receive preoperative chemotherapy. These latter tissues also expressed enhanced levels of ROS defenses with enhanced expression of superoxide dismutase. Higher levels of Oct-4 and CD133 were also observed in tumors obtained after neoadjuvant chemotherapy. Further studies provided evidence for the stabilization of Nrf2 due to reduced 26 S proteasome activity and increased p21 association as the driving signaling event that contributes to the transition from a high ROS quiescent state to a low ROS proliferating stage in drug-induced tumor stem cell enrichment.