TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis

Iriondo, Oihana; Liu, Yarong; Lee, Grace; Elhodaky, Mostafa; Jimenez, Christian; Lin, Li; Lang, Julie E.; Wang, Pin; Yu, Min

doi:10.1038/s41467-018-04460-w

Cited by 56 publications

(58 citation statements)

References 43 publications

(62 reference statements)

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“…Triple‐negative breast cancer (TNBC), as a special subtype, is considered to be most dangerous among breast cancers due to its high invasiveness and high malignancy . By developing multifunctional nanomaterials conjugated with targeting ligands, active‐targeted nanoprobes can improve the efficacy of diagnosis and therapy for cancers.…”

Section: Methodsmentioning

confidence: 99%

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T₁‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

Zhang

LIU

Gao

et al. 2018

Adv Healthcare Materials

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Section: Methodsmentioning

confidence: 99%

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T₁‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

Zhang

LIU

Gao

et al. 2018

Adv Healthcare Materials

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“…Inhibition of TAK1 up-regulates the p53-p21 signaling axis. TAK1 signaling in breast cancer cells contributes to tumor invasion, angiogenesis, and metastases, and TAK1 inactivation effectively blocks these responses 8,11,22,33 . To define the molecular targets of TAK1 in tumor cells, we thought to compare gene expression profiles in breast carcinoma (MDA-MB-231 and MCF7) and non-tumor MCF10A cell lines upon treatment with a selective TAK1 inhibitor 5Z-7-oxozeaenol 23 .…”

Section: Resultsmentioning

confidence: 99%

TAK1 signaling regulates p53 through a mechanism involving ribosomal stress

Zonneville

Wong

Limoge

et al. 2020

Sci Rep

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Triple-negative breast cancer (TNBC) is among the most aggressive forms of breast cancer with limited therapeutic options. TAK1 is implicated in aggressive behavior of TNBC, while means are not fully understood. Here, we report that pharmacological blockade of TAK1 signaling hampered ribosome biogenesis (RBG) by reducing expression of RBG regulators such as RRS1, while not changing expression of ribosomal core proteins. Notably, TAK1 blockade upregulated expression of p53 target genes in cell lines carrying wild type (wt) TP53 but not in p53-mutant cells, suggesting involvement of ribosomal stress in the response. Accordingly, p53 activation by blockade of TAK1 was prevented by depletion of ribosomal protein RPL11. Further, siRNA-mediated depletion of TAK1 or RELA resulted in RPL11-dependent activation of p53 signaling. Knockdown of RRS1 was sufficient to disrupt nucleolar structures and resulted in activation of p53. TCGA data showed that TNBCs express high levels of RBG regulators, and elevated RRS1 levels correlate with unfavorable prognosis. Cytotoxicity data showed that TNBC cell lines are more sensitive to TAK1 inhibitor compared to luminal and HER2 + cell lines. These results show that TAK1 regulates p53 activation by controlling RBG factors, and the TAK1ribosome axis is a potential therapeutic target in TNBC. Breast cancer (BC) is the second leading cause of cancer-related death in women 1. This heterogeneous disease includes multiple subtypes with distinct genetic, pathological and clinical features 2-4. Among BC subtypes, triple-negative breast cancers (TNBCs, ER/PR/HER2-negative) pose special challenges due to a lack of targeted therapy and overall poor prognosis 5 , underscoring a pressing need for better therapeutic options. Recent studies, including from our group, have implicated TGF-beta-activated kinase-1 (TAK1) in cancer progression and metastasis of breast, lung and colon cancers 6-12. TAK1 kinase, encoded by the MAP kinase kinase kinase gene (MAP3K7), mediates signaling by transforming growth factor beta (TGF-β) and pro-inflammatory cytokines 13-15. TAK1 activation involves E3-ubiquitin ligases cIAP1 and cIAP2 (cellular inhibitors of apoptosis, cIAPs), which mediate addition of K(lysine)-63-linked ubiquitin chains to RIP kinase and other signaling proteins 16. Activated TAK1 phosphorylates Ser/Thr residues in target proteins such as IKKα/CHUK, IKKβ/IKBKB and MKK3/6, leading to stimulation of MAPK (p38, ERK, JNK) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways 17. TAK1 protects cells from death-inducing agents by regulating cIAPs and cFLIP, a caspase-8 inhibitor 18,19 , and may also contribute to tumor resistance to radiation and chemotherapy 20,21. Preclinical studies with TNBC models have implicated TAK1 in tumor angiogenesis and metastases to the lungs and bone 11,22. Evidence also supports targeting TAK1 in treating colon and pancreatic cancers 9,12. Several pharmacological TAK1 inhibitors (TAK1-i) have been developed 23-25. The most potent TAK1...

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“…Trim8 directly ubiquitinates transforming growth factor-beta-activated kinase 1, thus promoting its phosphorylation and activation of downstream c-Jun N-terminal kinase/p38 and NF-κB signalling [11]. The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signalling pathways, including cell survival, apoptosis, autophagy, oxidative processes, cancer and the immune response [27][28][29][30]. TAK1 is a MAP3K protein and is considered a common upstream molecule in the MKK-JNK/p38 and IKK-NF-κB cascade, which induces activation of downstream JNK and NF-κB signalling [31][32][33].…”

Section: The Effect Of Trim8 On Hepatic I/r Is Mediated By Tak1 Activitymentioning

confidence: 99%

Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

Qiu¹,

Wang²,

Zhou³

et al. 2019

Int. J. Biol. Sci.

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Tripartite motif (Trim) 8 is an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is closely involved in innate immunity. However, the function of Trim8 in hepatic ischaemia/reperfusion (I/R) injury remains largely unknown. The aim of this study is to explore the role of Trim8 in hepatic I/R injury. Trim8 gene knockout mice and primary hepatocytes were used to construct hepatic I/R models. The effect of Trim8 on hepatic I/R injury was analysed via pathological and molecular analyses. The results indicated that Trim8 was significantly upregulated in liver of mice subjected to hepatic I/R injury. Trim8 knockout relieved hepatocyte injury triggered by I/R. Silencing of Trim8 expression alleviated hepatic inflammation responses and inhibited apoptosis in vitro and in vivo. Mechanistically, our study suggests that Trim8 deficiency may elicit hepatic protective effects by inhibiting the activation of transforming growth factor β-activated kinase 1 (TAK1)-p38/JNK signalling pathways. TAK1 was required for Trim8 function in hepatic I/R injury as TAK1 activation abolished Trim8 function in vitro. In conclusion, our study demonstrates that Trim8 deficiency plays a protective role in hepatic I/R injury by inhibiting the activation of TAK1-dependent signalling pathways.

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TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis

Cited by 56 publications

References 43 publications

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T₁‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T₁‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

TAK1 signaling regulates p53 through a mechanism involving ribosomal stress

Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

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TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis

Cited by 56 publications

References 43 publications

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T1‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T1‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

TAK1 signaling regulates p53 through a mechanism involving ribosomal stress

Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

Contact Info

Product

Resources

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ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T₁‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer

ZD2‐Engineered Gold Nanostar@Metal‐Organic Framework Nanoprobes for T₁‐Weighted Magnetic Resonance Imaging and Photothermal Therapy Specifically Toward Triple‐Negative Breast Cancer