The role of thioredoxin reductase 1 in melanoma metabolism and metastasis

Cassidy, Pamela B.; Honeggar, Matthew; Poerschke, Robyn L.; White, Karen H.; Florell, Scott R.; Andtbacka, Robert H.I.; Tross, Joycelyn; Anderson, Madeleine; Leachman, Sancy A.; Moos, Philip J.

doi:10.1111/pcmr.12398

Cited by 25 publications

(13 citation statements)

References 46 publications

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“…Selenium, an antioxidant micronutrient that can support the metabolism of ROS via the selenoproteins thioredoxin reductase and glutathione peroxidase (42), has actually been found to increase risk for non-melanoma skin cancer in high-risk populations (43). Using mice transgenic for hepatocyte growth factor, we previously reported that while a single topical treatment of selenomethionine (SeMet) to neonatal mice 24 h prior to UV-irradiation delayed melanoma formation, continued application of SeMet to the skin of these mice promoted the growth of early-stage tumors (44).…”

Section: Discussionmentioning

confidence: 99%

A Phase II Randomized Placebo-Controlled Trial of OralN-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative StressIn Vivo

Cassidy

Liu

Florell

et al. 2017

Cancer Prevention Research

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Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1–2 MED) using a solar simulator. One day later, the MED was re-determined and the irradiated nevus and a control un-irradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared to unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and post-intervention MED between those patients receiving NAC vs. placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type vs. loss of function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 h before nevus irradiation. Thus a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined.

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Section: Discussionmentioning

confidence: 99%

A Phase II Randomized Placebo-Controlled Trial of OralN-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative StressIn Vivo

Cassidy

Liu

Florell

et al. 2017

Cancer Prevention Research

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“…TrxR2 catalyzes the NADPH-dependent reduction of Trx2, which in its reduced state protects against elevated levels of ROS within the mitochondria 136 . It has been reported that TrxR2 expression is highly elevated in liver cancer 137 , TrxR1 levels on the other hand, the cytosolic isoform, are upregulated in many different cancers including breast 138 , thyroid 139 , prostate 140 , liver 141 , melanomas 142 and colorectal, where strong overexpression of both TrxR and Trx may correlate with overall tumor aggressiveness 143 , perhaps through the HIF-1 pathway 144 . The elevated level of the enzyme is an adaptation to the increased ROS production resulting from the higher metabolic activity of cancer cells 145 .…”

Section: Trx2/trxr2/prx3mentioning

confidence: 99%

Mitochondrial ROS control of cancer

Idelchik

Begley

et al. 2017

Seminars in Cancer Biology

259

169

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Mitochondria serve a primary role in energy maintenance but also function to govern levels of mitochondria-derived reactive oxygen species (mROS). ROS have long been established to play a critical role in tumorigenesis and are now considered to be integral to the regulation of diverse signaling networks that drive proliferation, tumor cell survival and malignant progression. mROS can damage DNA, activate oncogenes, block the function of tumor suppressors and drive migratory signaling. The mitochondrion's oxidant scavenging systems including SOD2, Grx2, GPrx, Trx and TrxR are key of the cellular redox tone. These mitochondrial antioxidant systems serve to tightly control the levels of the primary ROS signaling species, H2O2. The coordinated control of mROS levels is also coupled to the activity of the primary H2O2 consuming enzymes of the mitochondria which are reliant on the epitranscriptomic control of selenocysteine incorporation. This review highlights the interplay between these many oncogenic signaling networks, mROS and the H2O2 emitting and consuming capacity of the mitochondria.

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“…We also investigated correlations of TrxR activity and various clinical characteristics and features of patients with NSCLCs, such as metastasis, TNM stage, and histologic differentiation. Notably, previous studies have shown that TrxR plays a key role in mediating tumor metastasis 45,59,60 . In this study, the level of TrxR activity also increased significantly as NSCLCs progressed to a metastatic state.…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin Reductase as a Novel and Efficient Plasma Biomarker for the Detection of Non-Small Cell Lung Cancer: a Large-scale, Multicenter study

Chen

Yao

et al. 2019

Sci Rep

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There is an increased demand for efficient biomarkers for the diagnosis of non-small cell lung cancer (NSCLC). This study aimed to evaluate plasma levels of TrxR activity in a large population to confirm its validity and efficacy in NSCLC diagnosis. Blood samples were obtained from 1922 participants (638 cases of NSCLC, 555 cases of benign lung diseases (BLDs) and 729 sex- and age-matched healthy controls). The plasma levels of TrxR activity in patients with NSCLC (15.66 ± 11.44 U/ml) were significantly higher (P < 0.01) than in patients with BLDs (6.27 ± 3.78 U/ml) or healthy controls (2.05 ± 1.86 U/ml). The critical value of plasma TrxR activity levels for diagnosis of NSCLC was set at 10.18 U/ml, with a sensitivity of 71.6% and a specificity of 91.9%. The combination of NSE, CEA, CA19-9, Cyfra21-1, and TrxR was more effective for NSCLC diagnosis (sensitivity and specificity in the training set: 85.6%, 90.2%; validation set: 86.2%, 92.4%) than was each biomarker individually (P < 0.001). TrxR can also efficiently distinguish the metastatic status of the tumor, and it can further differentiate between various histological differentiations. Together, plasma TrxR activity was identified as a convenient, non-invasive, and efficient biomarker for the diagnosis of NSCLCs, particularly for discriminating between metastatic and non-metastatic tumors, or for histologic differentiation.

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The role of thioredoxin reductase 1 in melanoma metabolism and metastasis

Cited by 25 publications

References 46 publications

A Phase II Randomized Placebo-Controlled Trial of OralN-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative StressIn Vivo

A Phase II Randomized Placebo-Controlled Trial of OralN-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative StressIn Vivo

Mitochondrial ROS control of cancer

Thioredoxin Reductase as a Novel and Efficient Plasma Biomarker for the Detection of Non-Small Cell Lung Cancer: a Large-scale, Multicenter study

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