Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane

Clulow, James A.; Storck, Elisabeth M.; Lanyon‐Hogg, Thomas; Kalesh, Karunakaran A.; Jones, Lyn H.; Tate, Edward W.

doi:10.1039/c6cc08797c

Cited by 30 publications

(28 citation statements)

References 29 publications

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“…4b). Pull-down experiments with an activity-based probe (ABP) of SFN [21] in HBCx34 PDX tumor cells confirmed direct interaction of SFN with STAT3 in both antiestrogen and vehicletreated tumors ( Fig. 4c), establishing STAT3 as the likely target of SFX-01.…”

Section: Sfx-01 Targets Stat3 Signaling Which Is Activated By Antiesmentioning

confidence: 80%

“…The recent finding that SFN bound directly to STAT3 with high-affinity in BC cell lines [21] led us to investigate STAT3 as the target in antiestrogen treated PDX and endocrine resistant patient-derived samples. We show convincingly that binding occurs and, since SFN is known to react with cysteine residues [29], future research is warranted to determine precisely which STAT3 cysteine residues are targeted by SFN.…”

Section: Discussionmentioning

confidence: 99%

“…We next sought to determine the mechanism of sensitivity to SFX-01. The direct binding targets of SFN have been assessed in BC cell lines, identifying STAT3 and NF-κB subunits among the top high-affinity targets [21]. STAT3 was a particularly interesting target since ALDH + breast CSCs and tamoxifen resistant cells have previously been shown to express higher levels of phospho-STAT3 (active form), and inhibition of STAT3 reduces ALDH+ cell numbers and tumorigenicity [22,23].…”

Section: Sfx-01 Targets Stat3 Signaling Which Is Activated By Antiesmentioning

confidence: 99%

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Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

et al. 2020

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Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Here we investigate SFX-01, a stabilised formulation of sulforaphane (SFN), for its effects on breast CSC activity in ER+ preclinical models. SFX-01 reduced mammosphere formation efficiency (MFE) of ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and aldehyde dehydrogenase (ALDH) activity of patient-derived xenograft (PDX) tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor-initiating cell frequency in secondary transplants and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months' endocrine treatment of ER+ patients (n = 68) predicted poor prognosis. Our data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.

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Section: Sfx-01 Targets Stat3 Signaling Which Is Activated By Antiesmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Sfx-01 Targets Stat3 Signaling Which Is Activated By Antiesmentioning

confidence: 99%

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Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

et al. 2020

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“…Such keen interest in the molecule's potential can most likely be attributed to its excellent bioavailability [316,317] and an overt plurality of biological effects evidenced by over 200 high-confidence targets observed in breast cancer cells [318] and the potential for hermetic behaviors, as shown in several cell models [319]. While other isothiocyanates have not been studied as extensively as sulforaphane, its polypharmacological behavior may reflect a general signature of these chemicals, based on their chemical structure, lipophilicity, and reactivity [312].…”

Section: Sprouts: a Compelling Case For Drug Discovery?mentioning

confidence: 99%

Sprouts and Microgreens: Trends, Opportunities, and Horizons for Novel Research

et al. 2020

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Sprouts and microgreens have attracted tremendous interest across multiple disciplines in recent years. Here, we critically review the most recent advances to underscore research prospects and niches, and related challenges, not yet addressed or fully pursued. In particular, we report a number of themes that merit special attention as a result of their relevance to plant science, nutrition, health, and zootechnics: (1) species not yet or inadequately investigated, such as wild plants, and fruit tree strains; (2) abiotic and biotic factors, and biostimulants, for elicitation strategies and metabolic engineering; (3) sanitization and processing technologies to obtain high-quality products; (4) digestive fate and impact of bioactive elements, antinutrients, and allergens on human nutrition; (5) experimental challenges to researching health benefits; (6) the opportunity to generate natural product libraries for drug discovery; and (7) sprouts in animal feeding to improve both animal health and the nutritional value of animal products for the human diet. The convergence of different themes involving interdisciplinary competencies advocate fascinating research pursuits, for example, the elicitation of metabolic variants to generate natural product collections for identification and selection of bioactive chemicals with a role as nutraceuticals, key constituents of functional foods, or interactive partners of specific drugs.

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“…In FA, in vitro SFN treatment partially rescues the cellular phenotypic defects in frataxin-silenced motor neuron-like cells [92], in neural stem cells isolated from the KIKO FA mouse model [10] and in FA fibroblasts [77]. Despite this, SFN is actually not adopted in FA clinical trials, probably because of its off-target activity [93] and the low blood-brain barrier permeability [94]. In the same way, the synthetic compound CAT-4001, although never tested in humans, has shown promising results in FA mice by improving mitochondrial biogenesis of isolated DRG neurons [95,96].…”

Section: Therapeutic Intervention In the Regulation Of Nrf2-mediated mentioning

confidence: 99%

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

Rosa

Bertini

Piemonte

2020

IJMS

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Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

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Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane

Abstract: Protein targets of sulforaphane identified, and their affinities quantified, through competition-based chemical proteomics in two live breast cancer cell lines.

Cited by 30 publications

References 29 publications

Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

Sprouts and Microgreens: Trends, Opportunities, and Horizons for Novel Research

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

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