| 1. |
- Casares, L., et al.
(författare)
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The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity
- 2022
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Ingår i: Redox Biology. - : Elsevier BV. - 2213-2317. ; 51
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.
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| 2. |
- Eklund, Ella A, et al.
(författare)
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Assessing the prognostic value of KRAS mutation combined with tumor size in stage I-II non-small cell lung cancer: a retrospective analysis
- 2024
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Ingår i: FRONTIERS IN ONCOLOGY. - 2234-943X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: KRAS mutation status is a well-established independent prognostic factor in advanced non-small cell lung cancer (NSCLC), yet its role in early-stage disease is unclear. Here, we investigate the prognostic value of combining survival data on KRAS mutation status and tumor size in stage I-II NSCLC. Methods: We studied the combined impact of KRAS mutational status and tumor size on overall survival (OS) in patients with stage I-II NSCLC. We performed a retrospective study including 310 diagnosed patients with early (stage I-II) NSCLCs. All molecularly assessed patients diagnosed with stage I-II NSCLC between 2016-2018 in the V & auml;stra G & ouml;taland Region of western Sweden were screened in this multi-center retrospective study. The primary study outcome was overall survival. Results: Out of 310 patients with stage I-II NSCLC, 37% harbored an activating mutation in the KRAS gene. Our study confirmed staging and tumor size as prognostic factors. However, KRAS mutational status was not found to impact OS and there was no difference in the risk of death when combining KRAS mutational status and primary tumor size. Conclusions: In our patient cohort, KRAS mutations in combination with primary tumor size did not impact prognosis in stage I-II NSCLC.
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| 3. |
- Eklund, Ella A, et al.
(författare)
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KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer.
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016-2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207-1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124-2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148-0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.
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| 4. |
- Le Gal, Kristell, et al.
(författare)
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Antioxidants can increase melanoma metastasis in mice.
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 7:308
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Tidskriftsartikel (refereegranskat)abstract
- Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.
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| 5. |
- Le Gal, Kristell, et al.
(författare)
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Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice
- 2021
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Ingår i: Antioxidants. - : MDPI AG. - 2076-3921. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.
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| 6. |
- Malmhäll-Bah, Eric, et al.
(författare)
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Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis
- 2022
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4(+) T cells from GLC mice (CD4(+)GLCs). Spleen and joint draining lymph nodes (dLN) CD4(+)GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4(+)GLCs presented a complete signature of GARP(+)NRP1(+)IKZF2(+)FOXP3(+) regulatory T cells (Tregs) of thymic origin. Activation of the beta-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4(+) cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4(+) cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4(+)GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthri-togenic phenotype.
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| 7. |
- Moreno, R., et al.
(författare)
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Biotinylation of an acetylenic tricyclic bis(cyanoenone) lowers its potency as an NRF2 activator while creating a novel activity against BACH1
- 2022
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Ingår i: Free Radical Biology and Medicine. - : Elsevier BV. - 0891-5849. ; 191, s. 203-211
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor BACH1 regulates the expression of a variety of genes including genes involved in oxidative stress responses, inflammation, cell motility, cancer cell invasion and cancer metabolism. Based on this, BACH1 has become a promising therapeutic target in cancer (as anti-metastatic target) and also in chronic conditions linked to oxidative stress and inflammation, where BACH1 inhibitors share a therapeutic space with activators of transcription factor NRF2. However, while there is a growing number of NRF2 activators, there are only a few described BACH1 inhibitors/degraders. The synthetic acetylenic tricyclic bis(cyanoenone), (+/-)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3.4b,7,8,8a,9,10, 10a-octahydrophenanthrene-2,6-dicarbonitrile, TBE31 is a potent activator of NRF2 without any BACH1 activity. Herein we found that biotinylation of TBE31 greatly reduces its potency as NRF2 activator (50-75-fold less active) while acquiring a novel activity as a BACH1 degrader (100-200-fold more active). We demonstrate that TBE56, the biotinylated TBE31, interacts and promotes the degradation of BACH1 via a mechanism involving the E3 ligase FBXO22. TBE56 is a potent and sustained BACH1 degrader (50-fold more potent than hemin) and accordingly a powerful HMOX1 inducer. TBE56 degrades BACH1 in lung and breast cancer cells, impairing breast cancer cell migration and invasion in a BACH1-dependent manner, while TBE31 has no significant effect. Altogether, our study identifies that the biotinylation of TBE31 provides novel activities with potential therapeutic value, providing a rationale for further characterisation of this and related compounds.
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| 8. |
- Schoultz, Elin, et al.
(författare)
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Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor
- 2023
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Ingår i: ISCIENCE. - 2589-0042. ; 26:7
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Tidskriftsartikel (refereegranskat)abstract
- Cells of origin in cancer determine tumor phenotypes, but whether lineage-defining transcription factors might influence tissue specificity of tumorigenesis among organs with similar developmental traits are unknown. We demonstrate here that tumor development and progression markedly differ in lung and thyroid targeted by Braf mutation in Nkx2.1CreER(T2) mice heterozygous for Nkx2-1. In absence of tamoxifen, non-induced Nkx2.1CreER(T2);Braf(CA/+) mutants developed multiple full-blown lung adenocarcinomas with a latency of 1-3 months whereas thyroid tumors were rare and constrained, although minute Braf(CA) activation documented by variant allele sequencing was similar in both tissues. Induced oncogene activation accelerated neoplastic growth only in the lungs. By contrast, NKX2-1(+) progenitor cells were equally responsive to constitutive expression of mutant Braf during lung and thyroid development. Both lung and thyroid cells transiently downregulated NKX2-1 in early tumor stages. These results indicate that BRAF(V600E)-induced tumorigenesis obey organ-specific traits that might be differentially modified by a shared lineage factor.
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| 9. |
- Schwarz, Maria, et al.
(författare)
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Excessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P.
- 2023
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Ingår i: Nature communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Selenium homeostasis depends on hepatic biosynthesis of selenoprotein P (SELENOP) and SELENOP-mediated transport from the liver to e.g. the brain. In addition, the liver maintains copper homeostasis. Selenium and copper metabolism are inversely regulated, as increasing copper and decreasing selenium levels are observed in blood during aging and inflammation. Here we show that copper treatment increased intracellular selenium and SELENOP in hepatocytes and decreased extracellular SELENOP levels. Hepatic accumulation of copper is a characteristic of Wilson's disease. Accordingly, SELENOP levels were low in serum of Wilson's disease patients and Wilson's rats. Mechanistically, drugs targeting protein transport in the Golgi complex mimicked some of the effects observed, indicating a disrupting effect of excessive copper on intracellular SELENOP transport resulting in its accumulation in the late Golgi. Our data suggest that hepatic copper levels determine SELENOP release from the liver and may affect selenium transport to peripheral organs such as the brain.
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| 10. |
- Wiel, Clotilde, 1987, et al.
(författare)
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BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
- 2019
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 178:2, s. 330-345
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Tidskriftsartikel (refereegranskat)abstract
- For tumors to progress efficiently, cancer cells must overcome barriers of oxidative stress. Although dietary antioxidant supplementation or activation of endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis. Here, we show that long-term supplementation with the antioxidants N-acetylcysteine and vitamin E promotes KRAS-driven lung cancer metastasis. The antioxidants stimulate metastasis by reducing levels of free heme and stabilizing the transcription factor BACH1. BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. Targeting BACH1 normalized glycolysis and prevented antioxidant-induced metastasis, while increasing endogenous BACH1 expression stimulated glycolysis and promoted metastasis, also in the absence of antioxidants. We conclude that BACH1 stimulates glycolysis-dependent lung cancer metastasis and that BACH1 is activated under conditions of reduced oxidative stress.
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| 11. |
- Zhong, H., et al.
(författare)
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SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity
- 2023
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Ingår i: Oncogene. - 0950-9232. ; 42, s. 2183-2194
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Tidskriftsartikel (refereegranskat)abstract
- The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the Kras(G12D)-driven mouse LUAD model, we found that loss of Sox9 significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice. We demonstrate that SOX9 suppresses immune cell infiltration and functionally suppresses tumor associated CD8(+) T, natural killer and dendritic cells. These data were validated by flow cytometry, gene expression, RT-qPCR, and immunohistochemistry analyses in Kras(G12D)-driven murine LUAD, then confirmed by interrogating bulk and single-cell gene expression repertoires and immunohistochemistry in human LUAD. Notably, SOX9 significantly elevates collagen-related gene expression and substantially increases collagen fibers. We propose that SOX9 increases tumor stiffness and inhibits tumor-infiltrating dendritic cells, thereby suppressing CD8(+) T cell and NK cell infiltration and activity. Thus, SOX9 drives Kras(G12D)-driven lung tumor progression and inhibits anti-tumor immunity at least partly by modulating the tumor microenvironment.
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| 12. |
- Zou, Zhiyuan V., et al.
(författare)
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Antioxidants promote intestinal tumor progression in mice.
- 2021
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Ingår i: Antioxidants. - : MDPI AG. - 2076-3921. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.
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