Zhang Han, Chen Zheng, Miranda Roberto N, Medeiros L Jeffrey, McCarty Nami
Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, Texas.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2016 Nov 1;76(21):6410-6423. doi: 10.1158/0008-5472.CAN-16-0595. Epub 2016 Aug 3.
Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-κB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-κB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-κB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-κB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410-23. ©2016 AACR.
转谷氨酰胺酶TG2的表达与套细胞淋巴瘤（MCL）细胞中NF-κB的组成性激活及化疗耐药相关。TG2与NF-κB组分形成复合物，但一直缺乏可用于改善治疗反应的机制性见解。在当前研究中，我们通过发现TG2在通过诱导IL6触发耐药MCL细胞自噬中发挥的意外作用来解决这一问题。CRISPR介导的TG2沉默延迟了细胞凋亡，而过表达TG2则促进了肿瘤进展。在应激条件下，TG2和IL6介导自噬形成增强以促进MCL细胞存活。有趣的是，参与自噬体延伸的自噬产物ATG5正向调节TG2/NF-κB/IL6信号传导，提示存在正反馈环。我们的结果揭示了MCL细胞中TG2/NF-κB和IL6/STAT3信号传导与自噬调节的相互关联网络，破坏该网络可能提供一种有前景的治疗策略。《癌症研究》；76(21)；6410 - 23。©2016美国癌症研究协会。
