Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance

Takahashi, Nobuaki; Chen, Hsing-Yu; Harris, Isaac S.; Stover, Daniel G.; Selfors, Laura M.; Bronson, Roderick T.; Raedt, Thomas De; Cichowski, Karen; Welm, Alana L.; Mori, Yasuo; Mills, Gordon B.; Brugge, Joan S.

doi:10.1016/j.ccell.2018.05.001

Cited by 205 publications

(196 citation statements)

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“…As a result, the top three differentially expressed genes, namely transient receptor potential cation channel subfamily A member 1 ( TRPA1 ), tetraspanin 17 ( TSPAN17 ) and secretogranin V ( SCG5 ), with the minimum required energy to hybridize with tRF-T11 at their 3’ UTR regions of mRNA, were considered as the potential targets for further experimental validation (Fig 2e). Among these three genes, TRPA1 , a new target recently unveiled by Takahashi et al 24 for cancer therapies, which acts by triggering a noncanonical oxidative stress defense mechanism of tumor suppression, was dramatically downregulated in A2780 cells (by approximately 75%) in a dose-dependent manner by tRF-T11 mimic treatment (Fig 2j, g), while the mRNA levels of the other two targets did not vary significantly (Fig 2f). Furthermore, a marked decrease of over 50% in the protein expression level of TRPA1 was also observed in A2780 cells treated with tRF-T11 mimic (Fig 2h, i), which may act as a translational repressor of the TRPA1 gene by acting like a miRNA in human OVCA cells.…”

Section: Figurementioning

confidence: 89%

Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

Cao

Yan

Zhang

et al. 2019

Preprint

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Zhi-Hong Jiang) 16 2 † These authors contributed equally to this work. 17 18 3 Plants containing countless chemical constituent have benefited mankind since 19 the origin of life. Although secondary metabolites in plants, such as morphine, 20 artemisinin and taxol, have been developed as therapeutic drugs for clinical 21 therapy, few study focuses on the pharmacological activities of plant small RNAs 22 with function of cross-kingdom regulations. Yew is widely considered as a 23 "superstar" plant due to the discovery of paclitaxel, or taxol, which is a 24 well-known natural drug for the treatment of multiple types of cancer 1 . Here we 25 show the surprising finding that an RNA fragment, named tRF-T11, derived 26 from tRNA His(GUG) of Chinese yew strongly suppressed human ovarian cancer 27 progression. In A2780 cells, tRF-T11 mimic (a double-stranded RNA with 28 tRF-T11 as antisense chain) exhibited potent cytotoxicity comparable to that of 29 taxol, but no significant cytotoxicity to normal ovarian surface epithelial cells. 30 Moreover, the cytotoxicity of tRF-T11 mimic is 80-fold stronger than that of 31 taxol in taxol-resistant A2780 cells. Bioinformatic and molecular biological 32 studies revealed that tRF-T11 targets transient receptor potential cation channel 33 subfamily A member 1 (TRPA1) to inhibit its expression levels. In a further in 34 4 vivo investigation, the growth rate of ovarian tumor xenografts in nude mice was 35 significantly reduced by treatment with tRF-T11 mimic, and the TRPA1 protein 36 expression in tumors treated with tRF-T11 mimic was also down-regulated. Our 37 findings are the first to provide evidence that plant-derived tRFs can regulate 38 the expression of target genes in vitro and in vivo, indicating that they may 39 become as a new source of druggable siRNA. Moreover, this discovery 40 demonstrated a pilot example of an innovative approach for not only identifying 41 pharmacologically-active tRFs from plants, but also for improving the efficiency 42 and possibilities of discovering new drug target. 43

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Section: Figurementioning

confidence: 89%

Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

Cao

Yan

Zhang

et al. 2019

Preprint

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“…Antioxidant pathways are necessary for tumorigenesis (DeNicola et al, 2011;Harris et al, 2015) and tumor progression (Deblois et al, 2016;Takahashi et al, 2018). Recent studies have shown that residual tumor cells experience oxidative stress (Havas et al, 2017;Viale et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

NRF2-dependent metabolic reprogramming is required for tumor recurrence following oncogene inhibition

Fox

Lupo

Noteware

et al. 2019

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Oncogenic signaling pathways both directly and indirectly regulate anabolic metabolism, and this is required for tumor growth. Targeted therapies that inhibit oncogenic signaling have dramatic impacts on cellular metabolism. However, it is not known whether the acquisition of resistance to these therapies is associated with -or driven by -alterations in cellular metabolism. To address this, we used a conditional mouse model of Her2-driven breast cancer to study metabolic adaptations following Her2 inhibition, during residual disease, and after tumor recurrence. We found that Her2 downregulation caused widespread changes in cellular metabolism, culminating in oxidative stress. Tumor cells adapted to this metabolic stress by upregulation of the antioxidant transcription factor, NRF2. Constitutive NRF2 expression persisted during residual disease and tumor recurrence, and NRF2 was both sufficient to promote tumor recurrence, and necessary for recurrent tumor growth. These results are supported by clinical data showing that the NRF2 transcriptional program is activated in recurrent breast tumors, and that NRF2 is associated with poor prognosis in patients with breast cancer. Mechanistically, NRF2 signaling in recurrent tumors induced metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. Finally, this NRF2-driven metabolic state rendered recurrent tumor cells sensitive to glutaminase inhibition, suggesting that NRF2-high recurrent tumors can be therapeutically targeted. Together, these data provide evidence that NRF2-driven metabolic reprogramming is required for breast cancer recurrence following oncogene inhibition. SignificanceAlthough tumor recurrence is the leading cause of mortality in breast cancer, the cellular properties that allow tumor cells to evade therapy and form recurrent tumors remain largely uncharacterized. Similarly, very little is known about how tumor metabolism changes following therapy, or whether alterations in cellular metabolism drive tumor recurrence. In this study, we identify the antioxidant transcription factor NRF2 as a critical positive regulator of breast cancer recurrence. We find that NRF2-dependent metabolic reprogramming is both sufficient and required to promote tumor recurrence. Additionally, we demonstrate that the NRF2-driven metabolic state renders recurrent tumors sensitive to glutaminase inhibitors, suggesting a novel therapeutic approach for the treatment of recurrent breast cancer. KeywordsNRF2, ROS, Tumor metabolism, Residual disease, Breast cancer recurrence, Her2 ! 3!

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“…4B). Recognizing oxidative-stress heterogeneities in 3D spheroids (21,22,64), we used the genetically-encoded sensor HyPer-2 (65) together with a novel mRFP1-NRF2 reporter (NRF2rep) to colocalize intracellular H2O2 with stabilized NRF2 (see Materials and Methods and fig. S7).…”

Section: Nrf2 and P53 Are Coordinately Stabilized By Sporadic Oxidatimentioning

confidence: 99%

Sporadic activation of an oxidative stress-dependent NRF2–p53 signaling network in breast epithelial spheroids and premalignancies

Pereira

Burns

Lee

et al. 2019

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ABSTRACTBreast–mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell-regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal 3D spheroids are cultured in basement membrane, and prior transcriptomic analyses identified a state associated with stress tolerance and poor response to anticancer therapeutics. Here, we examined the regulation of this state and found that it is jointly coordinated by the NRF2 and p53 pathways, which are co-stabilized by spontaneous oxidative stress within the 3D cultures. Inhibition of NRF2 or p53 individually disrupts some of the transcripts defining the regulatory state but does not yield a notable phenotype in nontransformed breast epithelial cells. In contrast, combined perturbation prevents 3D growth in an oxidative stress-dependent manner. By integrating systems models of NRF2 and p53 signaling together as a single oxidative-stress network, we recapitulate these observations and make predictions about oxidative stress profiles during 3D growth. Similar coordination of NRF2 and p53 signaling is observed in normal breast epithelial tissue and hormone-negative ductal carcinoma in situ lesions. However, the pathways are uncoupled in triple-negative breast cancer, a subtype in which p53 is usually mutated. Using the integrated model, we reconcile the different NRF2-knockdown phenotypes of triple-negative cancer lines with their inferred handling of oxidative stress. Our results point to an oxidative stress-tolerance network that is important for single cells during glandular development and the early stages of breast cancer.One Sentence SummaryReactive oxygen species co-stabilize a non-oncogene and a tumor suppressor for triple-negative breast cancer when cells are surrounded by basement-membrane ECM.

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Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance

Cited by 205 publications

References 54 publications

Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

NRF2-dependent metabolic reprogramming is required for tumor recurrence following oncogene inhibition

Sporadic activation of an oxidative stress-dependent NRF2–p53 signaling network in breast epithelial spheroids and premalignancies

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