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Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-κB signaling
Ying Qu, … , Ning-Hui Cheng, Xiaojiang Cui
Ying Qu, … , Ning-Hui Cheng, Xiaojiang Cui
Published December 1, 2010
Citation Information: J Clin Invest. 2011;121(1):212-225. https://doi.org/10.1172/JCI43144.
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Research Article Oncology

Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-κB signaling

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Abstract

Cancer cells have an efficient antioxidant system to counteract their increased generation of ROS. However, whether this ability to survive high levels of ROS has an important role in the growth and metastasis of tumors is not well understood. Here, we demonstrate that the redox protein thioredoxin-like 2 (TXNL2) regulates the growth and metastasis of human breast cancer cells through a redox signaling mechanism. TXNL2 was found to be overexpressed in human cancers, including breast cancers. Knockdown of TXNL2 in human breast cancer cell lines increased ROS levels and reduced NF-κB activity, resulting in inhibition of in vitro proliferation, survival, and invasion. In addition, TXNL2 knockdown inhibited tumorigenesis and metastasis of these cells upon transplantation into immunodeficient mice. Furthermore, analysis of primary breast cancer samples demonstrated that enhanced TXNL2 expression correlated with metastasis to the lung and brain and with decreased overall patient survival. Our studies provided insight into redox-based mechanisms underlying tumor growth and metastasis and suggest that TXNL2 could be a target for treatment of breast cancer.

Authors

Ying Qu, Jinhua Wang, Partha S. Ray, Hua Guo, Jian Huang, Miyung Shin-Sim, Bolanle A. Bukoye, Bingya Liu, Adrian V. Lee, Xin Lin, Peng Huang, John W. Martens, Armando E. Giuliano, Ning Zhang, Ning-Hui Cheng, Xiaojiang Cui

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Figure 7

NF-κB is essential for the effects of TXNL2 on cell survival and EMT.

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NF-κB is essential for the effects of TXNL2 on cell survival and EMT.
(A...
(A) Morphologies of control MDA-MB-231 and BT549 cells treated with the IKK inhibitor BMS-345541 (BMS) or DMSO for 24 hours are shown (original magnification, ×200). (B) Expression of NF-κB–regulated genes was measured using RT-PCR in MDA-MB-231 cells treated with BMS-345541 or DMSO. (C) Total Akt and p-Akt levels in control and TXNL2-KD MDA-MB-231 cells were measured using Western blotting. (D) Apoptosis was measured using Annexin V/PI staining in MDA-MB-231 cells treated with vehicle (ctrl), AI-IV, or BMS. Data represent mean ± SD of 3 independent experiments. Growth curves of cells treated with or without inhibitors are plotted. (E) Akt activation and EMT markers (E-cadherin and vimentin) in IκBα-SR–overexpressing and control MDA-MB-231 cells were measured using Western blotting. Cell morphologies are shown (original magnification, ×200). (F) The expression of NF-κB and Akt after BMS or AI-IV treatment was examined using Western blotting. (G) A schematic diagram of TXNL2 signaling. Broken lines indicate pathways, based on previous reports. The question mark denotes currently unknown mechanisms.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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