γ-Tocotrienol inhibits oxidative phosphorylation and triggers apoptosis by inhibiting mitochondrial complex I subunit NDUFB8 and complex II subunit SDHB

Wang, Haixia; Luo, Juntao; Tian, Wen; Yan, Wenqing; Song, Ge; Zhang, YaHui; Sun, Wenguang

doi:10.1016/j.tox.2019.01.018

Cited by 25 publications

(26 citation statements)

References 47 publications

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“…However, literature data addressing the role of mitochondrial metabolism in the anti-tumor effects of TTs are still poor. Wang et al have recently reported that γ-TT can inhibit OXPHOS in gastric adenocarcinoma cells by targeting mitochondrial complex I and II, while δ-TT suppressed mitochondrial activity and ATP production in HER-2 overexpressing breast cancer [ 39 , 40 ]. We have also shown that mitochondrial structural and functional impairment is deeply implicated in δ-TT anti-prostate cancer activity [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

et al. 2021

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Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

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Section: Discussionmentioning

confidence: 99%

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

et al. 2021

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“… 28 , 29 , 30 , 31 Regarding TTs, the γ isoform has been reported to trigger mitochondrial dysfunction‐ and oxidative imbalance‐associated apoptosis in gastric adenocarcinoma cells, as well as to sensitize colorectal cancer cells to TRAIL proapoptotic activity via ROS overproduction. 32 , 33 Similarly, δ‐TT can cause ROS‐mediated cytotoxicity in various models of breast and prostate cancer, 11 , 34 while α‐tocopheryl succinate, a redox‐silent Vitamin E analogue, has been demonstrated to stimulate cytochrome c release in neuroblastoma through a severe alteration of redox homeostasis. 35 In OC cells, we observed that δ‐TT promotes mitochondrial ROS generation and that NAC can successfully rescue cell viability by preventing caspase 3 and PARP cleavage, thus highlighting the involvement of oxidative stress in the apoptosis induced by the compound.…”

Section: Discussionmentioning

confidence: 99%

δ‐Tocotrienol sensitizes and re‐sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK‐mediated apoptosis

et al. 2021

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Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women worldwide, representing the deadliest form of gynaecologic malignancy. 1 Due to the lack of early symptoms and consequent difficulties in detection, most OC patients are diagnosed at advanced stages. 2,3 Current standard treatment for patients with advanced OC includes primary tumour cytoreductive surgery followed by chemotherapy. 4 Platinum is commonly used in OC chemotherapy. 4 The efficacy of this DNA-damaging agent seems to be correlated with its ability to inhibit the proliferation and induce apoptosis of cancer cells. However, despite being initially responsive, about 70% of patients

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“…Due to the damaged mitochondrial structure, the present study then examined whether the electron transfer chain (ETC) complexes were also affected. The expression levels of NADH dehydrogenase subunit 6, SDHB and COX6B1 were analyzed, which all participate in mitochondria oxidative phosphorylation (OXPHOS) (33)(34)(35). The IHC results revealed that, compared with in normal tissues, the levels of NADH dehydrogenase subunit 6 and SDHB in glioma tissues were significantly lower, while COX6B1 expression in glioma tissues was significantly higher compared with that in para-NTs ( Fig.…”

Section: Inflammation In Gliomamentioning

confidence: 98%

Glioma cells are resistant to inflammation‑induced alterations of mitochondrial dynamics

et al. 2020

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Accumulating evidence suggests that inflammation is present in solid tumors. However, it is poorly understood whether inflammation exists in glioma and how it affects the metabolic signature of glioma. By analyzing immunohistochemical data and gene expression data downloaded from bioinformatic datasets, the present study revealed an accumulation of inflammatory cells in glioma, activation of microglia, upregulation of proinflammatory factors (including IL-6, IL-8, hypoxia-inducible factor-1α, STAT3, NF-κB1 and NF-κB2), destruction of mitochondrial structure and altered expression levels of electron transfer chain complexes and metabolic enzymes. By monitoring glioma cells following proinflammatory stimulation, the current study observed a remodeling of their mitochondrial network via mitochondrial fission. More than half of the mitochondria presented ring-shaped or spherical morphologies. Transmission electron microscopic analyses revealed mitochondrial swelling with partial or total cristolysis. Furthermore, proinflammatory stimuli resulted in increased generation of reactive oxygen species, decreased mitochondrial membrane potential and reprogrammed metabolism. The defective mitochondria were not eliminated via mitophagy. However, cell viability was not affected, and apoptosis was decreased in glioma cells after proinflammatory stimuli. Overall, the present findings suggested that inflammation may be present in glioma and that glioma cells may be resistant to inflammation-induced mitochondrial dysfunction.

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γ-Tocotrienol inhibits oxidative phosphorylation and triggers apoptosis by inhibiting mitochondrial complex I subunit NDUFB8 and complex II subunit SDHB

Cited by 25 publications

References 47 publications

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

δ‐Tocotrienol sensitizes and re‐sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK‐mediated apoptosis

Glioma cells are resistant to inflammation‑induced alterations of mitochondrial dynamics

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