Sulforaphane induces autophagy through ERK activation in neuronal cells

Jo, Chulman; Kim, Sunhyo; Cho, Sun-Jung; Choi, Kang-Duk; Yun, Sang-Moon; Koh, Young Ho; Johnson, Gail V.W.; Park, Sang Ick

doi:10.1016/j.febslet.2014.06.036

Cited by 61 publications

(39 citation statements)

References 44 publications

(64 reference statements)

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“…These data are consistent with those obtained in a previous study (16). One possibility for this activation of ERK1/2 may result from the production of reactive oxygen species (ROS) by participation of SFN (46). SFN administration to prostate cancer cells led to ROS generation, which induced apoptosis and metastatic inhibition (14).…”

Section: Discussionsupporting

confidence: 91%

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

et al. 2015

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Abstract. Advanced prostate cancer has highly invasive potential, which may lead to metastasis associated with poor prognosis. Sulforaphane (SFN), abundant in cruciferous vegetables, exhibited effective resistance to carcinogenesis in a variety of tumors. The aim of the present study was to investigate whether SFN inhibited invasion in human prostate cancer cells via sustained activation of ERK1/2 and downstream signaling by an invasion assay, gelatin zymography and western blot analysis. The results showed that SFN inhibited invasion and we characterized the underlying mechanisms in human DU145 prostate cancer cells. SFN (15 µM) changed cell morphology leading to short-cell pseudopodia which may suppress tumor migration and invasion. The Transwell assay showed that SFN phosphorylated ERK1/2 in a doseand time-dependent manner and significantly inhibited cell invasion, while the effect was reduced by the ERK1/2 blocker PD98059 (25 µM). Furthermore, these effects contributed to the upregulation of E-cadherin and the downregulation of CD44v6 and were eradicated by PD98059. Western blot analysis and gelatin zymography showed that SFN decreased the expression and activity of MMP-2. Thus, SFN inhibited invasion by activating ERK1/2 to upregulate E-cadherin and downregulate CD44v6, thereby reducing MMP-2 expression and activity. E-cadherin is an invasion inhibitor, while CD44v6 and MMP-2 are invasion promoters. Therefore, SFN is a prospective therapeutic agent that may be used to prevent invasion in prostate cancer.

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Section: Discussionsupporting

confidence: 91%

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

et al. 2015

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“…Lower panels, immunohistochemistry of a-SYN and NQO1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars NRF2 activator, that also promotes autophagy by regulating ERK (36) or AMPK (79). In any case, these observations collectively indicate that DMF regulates autophagy, at least in part, by regulating the NRF2/p62 axis.…”

Section: Lastres-becker Et Almentioning

confidence: 97%

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

Lastres‐Becker

García-Yagüe

Scannevin

et al. 2016

Antioxidants & Redox Signaling

230

223

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Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, a-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against a-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human a-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61-77.

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“…86 The activation of general autophagy by sulforaphane is an example of great relevance as it occurs via a ROS-dependent mechanism and independently of its effects on Nrf2. 90 On the other hand, PMI promotes a targeted autophagic degradation of mitochondria without affecting general autophagy. 85 Notably, our preliminary results suggest that sulforaphane does not mediate similar effects on mitophagy, despite activating Nrf2 and up-regulating the expression of p62/SQSTM1.…”

Section: Nrf2 Inducers and The Anterograde Regulation Of Cell Mitophagymentioning

confidence: 99%

The pharmacological regulation of cellular mitophagy

2017

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Small molecules are pharmacological tools of considerable value in dissecting complex biological processes and identifying potential therapeutic interventions.Recently, the cellular quality control process of mitophagy attracted considerable research interest, however, the limited availability of suitable chemical probes restricted our understanding of the molecular mechanisms involved.Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (e.g. FCCP/CCCP), or the use of Antimycin A/Oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis, and therefore limit the scope for dissection of subtle, bio-energy related regulatory phenomena.Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation.We have therefore summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications.

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Sulforaphane induces autophagy through ERK activation in neuronal cells

Cited by 61 publications

References 44 publications

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

The pharmacological regulation of cellular mitophagy

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