Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway

Wang, Huixiang; Zhao, Xiaoli; Ni, Chengxiang; Dai, Yinmei; Guo, Yan

doi:10.3892/mmr.2018.8823

Cited by 22 publications

(30 citation statements)

References 69 publications

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“…Increasing evidence indicates that mitochondrial fission promotes the initiation of mitochondrial apoptosis . Our transmission electron microscopy assay revealed that mitochondria presented as elongated filamentous structures in control cells, but exhibited small and punctate mitochondria in IR‐783‐treated cells (Figure A).…”

Section: Resultsmentioning

confidence: 78%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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IR‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR‐783 has not been well demonstrated. In this study, we showed that IR‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA‐MB‐231 cells to IR‐783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR‐783‐mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR‐783 markedly inhibited tumour growth and induced apoptosis in an MDA‐MB‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR‐783 and provided novel perspectives for the application of IR‐783 in the treatment of breast cancer.

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Section: Resultsmentioning

confidence: 78%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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“…DRP1 phosphorylations are modulated by the ERK1/2, PKA and JNK signal pathways [26,27,28,29,30]. Furthermore, CDDO-Me influences ERK1/2 [20,31] and JNK phosphorylations [32,33].…”

Section: Resultsmentioning

confidence: 99%

“…DRP1-S616 phosphorylation is regulated by the ERK1/2 and JNK signal pathways, which facilitate mitochondrial fission [27,29,30]. However, DRP1-S637 phosphorylation by PKA leads to detached DRP1 from mitochondria, thus inhibiting mitochondrial fission [26,28].…”

Section: Discussionmentioning

confidence: 99%

CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

Kim

Park

Choi

et al. 2019

Cells

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2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that exhibits promising anti-cancer, anti-inflammatory, antioxidant and neuroprotective activities. In addition, CDDO-Me affects cellular differentiation and cell cycle arrest, and irreversibly inhibits Lon protease-1 (LONP1). In the present study, we evaluate the effects of CDDO-Me on mitochondrial dynamics and its downstream effectors in order to understand the underlying mechanism of the neuronal death following status epilepticus (SE, a prolonged seizure activity). CDDO-Me increased dynamin-related proteins 1 (DRP1)-serine 616 phosphorylation via activating extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but not protein kinase A (PKA) or protein phosphatases (PPs). In addition, CDDO-Me facilitated DRP1-mediated mitochondrial fissions, which selectively attenuated SE-induced CA1 neuronal death. Unlike CDDO-Me, LONP1 knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of DRP1, ERK1/2, JNK and PP2B. LONP1 knockdown could not inhibit SE-induced mitochondrial elongation in CA1 neurons. Co-treatment of CDDO-Me with LONP1 siRNA ameliorated only CA1 neuronal death, concomitant with abrogation of mitochondrial elongation induced by SE. Thus, our findings suggest that CDDO-Me may selectively attenuate SE-induced CA1 neuronal death by rescuing the abnormal mitochondrial machinery, independent of LONP1 activity.

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“…In acute myocardial ischemia reperfusion injury and chronic heart fibrosis, activated JNK promotes mitochondrial fragmentation and cardiomyocyte death. Similarly, in liver cancer, rectal cancer, gastric cancer,49 endometriosis58 and cervical cancer,59 the JNK pathway has been identified as the upstream factor for mitochondrial fragmentation activation. In agreement with previous studies, we also found that inhibition of the JNK pathway repressed Drp1 expression and attenuated mitochondrial fragmentation.…”

Section: Discussionmentioning

confidence: 99%

<p>Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK–Drp1 axis</p>

Ouyang¹,

Zhou²,

Wang³

2019

OTT

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Background and objective Mst1-Hippo pathway and mitochondrial fragmentation participate in the progression of several types of cancers. However, their roles in breast cancer requires investigation. The aim of our study is to determine whether Mst1 overexpression regulates the viability of breast cancer cells via modulating mitochondrial fragmentation. Materials and methods TUNEL staining, MTT assay and Western blotting were used to detect cancer cell death. Adenovirus-loaded Mst1 was transfected into cells to overexpress Mst1. Mitochondrial fragmentation was observed via immunofluorescence staining and Western blotting. Pathway blocker was used to detect whether Mst1 modulated cell death and mitochondrial fragmentation via JNK signaling pathway. Results Our data showed that Mst1 overexpression promoted breast cancer cell death in a manner dependent on mitochondrial apoptosis. Mitochondrial oxidative stress, energy metabolism disorder, mitochondrial cyt- c liberation and mitochondrial apoptosis activation were observed after Mst1 overexpression. Furthermore, we demonstrated that Mst1 overexpression activated mitochondrial stress via triggering Drp1-related mitochondrial fragmentation, and that inhibition of Drp1-related mitochondrial fragmentation abrogated the proapoptotic effect of Mst1 overexpression on breast cancer cells. To this end, we found that Mst1 modulated Drp1 expression via the JNK signaling pathway, and that blockade of the JNK pathway attenuated mitochondrial stress and repressed apoptosis in Mst1-overexpressed cells. Conclusion Altogether, our results identified a tumor suppressive role for Mst1 overexpression in breast cancer via activation of the JNK–Drp1 axis and subsequent initiation of fatal mitochondrial fragmentation. Given these findings, strategies to enhance Mst1 activity and elevate the JNK–Drp1–mitochondrial fragmentation cascade have clinical benefits for patients with breast cancer.

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Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway

Cited by 22 publications

References 69 publications

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

<p>Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK–Drp1 axis</p>

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Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway

Cited by 22 publications

References 69 publications

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1

<p>Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK&ndash;Drp1 axis</p>

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<p>Mst1-Hippo pathway triggers breast cancer apoptosis via inducing mitochondrial fragmentation in a manner dependent on JNK–Drp1 axis</p>