IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway

Yang, Yi; Yy, Wang; Hsiao, Michael; Lo, Steven; Chang, Yu Chan; Jan, Yi-Hua; Lai, Tsung‐Ching; Lee, Yi Chen; Hsieh, Ya Ching; Yuan, Shyng Shiou F.

doi:10.1016/j.canlet.2020.04.025

Cited by 21 publications

(19 citation statements)

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“…Intracellular ROS production has been reported to be related to various stresses. ROS affects cell apoptosis, migration, and invasion, which are generated by mitochondrial metabolism [ 25 ]. To elucidate whether Rh1 modulates the production of ROS in MDA-MB-231 cells, cells were treated with various concentrations of Rh1 for 24 h. Thereafter, ROS levels were analyzed by DCF-DA staining.…”

Section: Resultsmentioning

confidence: 99%

Ginsenoside Rh1 Prevents Migration and Invasion through Mitochondrial ROS-Mediated Inhibition of STAT3/NF-κB Signaling in MDA-MB-231 Cells

Jin

Huynh

Myung

et al. 2021

IJMS

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Breast cancer (BC) a very common cancer in women worldwide. Triple negative breast cancer (TNBC) has been shown to have a poor prognosis with a high level of tumor metastatic spread. Here, the inhibitory effects of ginsenoside-Rh1 (Rh1) on BC metastasis, and its underlying signaling pathway in TNBC were investigated. Rh1-treated MDA-MB-231 cells were analyzed for metastasis using a wound healing assay, transwell migration and invasion assay, western blotting, and qRT-PCR. Rh1 treatment significantly inhibited BC metastasis by inhibiting the both protein and mRNA levels of MMP2, MMP9, and VEGF-A. Further, Rh1-mediated inhibitory effect on BC migration was associated with mitochondrial ROS generation. Rh1 treatment significantly eliminated STAT3 phosphorylation and NF-κB transactivation to downregulate metastatic factors, such as MMP2, MMP9, and VEGF-A. In addition, Mito-TEMPO treatment reversed Rh1 effects on the activation of STAT3, NF-κB, and their transcriptional targets. Rh1 further enhanced the inhibitory effects of STAT3 or NF-κB specific inhibitor, stattic or BAY 11-7082 on MMP2, MMP9, and VEGF-A expression, respectively. In summary, our results revealed the potent anticancer effect of Rh1 on TNBC migration and invasion through mtROS-mediated inhibition of STAT3 and NF-κB signaling.

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Section: Resultsmentioning

confidence: 99%

Ginsenoside Rh1 Prevents Migration and Invasion through Mitochondrial ROS-Mediated Inhibition of STAT3/NF-κB Signaling in MDA-MB-231 Cells

Jin

Huynh

Myung

et al. 2021

IJMS

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“…We evaluated the direct interaction partners of HTR3C using the BioGRID website and found that inositol monophosphatase domain-containing 1 (IMPAD1) interacts with HTR3C (Supplementary Table 2 ). IMPAD1 acts as a mitochondrial electron transport inhibitor and promotes lung cancer metastasis [ 16 ]. We further examined the correlation between HTR3C and IMPAD1 mRNA levels, which showed that HTR3C mRNA levels were positively correlated with IMPAD1 mRNA levels in lung cancer tissues (GSE31210; Figure 2(d) ).…”

Section: Resultsmentioning

confidence: 99%

“…Our data showed that HTR3C expression was significantly associated with lymph node metastasis, distant metastasis, and recurrence in lung cancer patients. In the BioGRID dataset, HTR3C interaction with the oncogene IMPAD1 was shown to promote lung cancer metastasis via the inhibition of mitochondrial electron transport [ 16 ]. The high HTR3C /high IMPAD1 expression cohort showed a significant decrease in OS compared with the low HTR3C /low IMPAD1 expression cohort ( Figure 2(e) ).…”

Section: Discussionmentioning

confidence: 99%

Potential Clinical Value of 5-Hydroxytryptamine Receptor 3C as a Prognostic Biomarker for Lung Cancer

Chen

Huang

Lee

et al. 2021

Journal of Oncology

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Ion channels and pumps not only regulate membrane potential, ion homeostasis, and electric signaling in excitable cells but also contribute to cell proliferation, migration, apoptosis, and differentiation. Channel proteins and ion pumps can form macromolecular complexes with signaling molecules, including growth factors and cell adhesion molecules. Serotonin (5-hydroxytryptamine (5-HT)) promotes the proliferation of various cancer cell types mediated through the activation of the 5-HT receptor (HTR). Only HTR3 is a ligand-gated ion channel. However, the role of the HTR3 family of HTRs in lung cancer has not been adequately evaluated. We evaluated the relationship between the HTR3 family of HTRs and lung cancer patients’ survival using Kaplan–Meier analyses and examined the expression levels of target proteins using immunohistochemistry. In this study, we found that HTR3C was amplified with high frequency in lung cancer patients, and HTR3C protein expression levels were significantly associated with lymph node metastasis and distant metastasis in lung cancer tissues. Survival analysis using the log-rank test demonstrated a decrease in disease-free survival (DFS) and overall survival (OS) rates among the high-level HTR3C expression group compared with the low-level HTR3C expression group. We also evaluated the risk factors associated with lung cancer. The univariate and multivariate analyses of DFS and OS showed that HTR3C expression was a significant predictor of patient outcomes. Taken together, these data demonstrated that HTR3C expression levels were associated with poor DFS and OS in lung cancer patients, indicating that HTR3C can serve as a useful predictive biomarker for lung cancer.

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“…Furthermore, a previous study has shown that AMPK serves an important role in regulating mitochondrial function (30). Similarly, mitochondrial damage leads to ROS production, activating AMPK, and AMPK affects mitochondrial function in return (49).…”

Section: Discussionmentioning

confidence: 97%

Triclosan induces ROS‑dependent cell death and autophagy in A375 melanoma cells

et al. 2020

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Melanoma is a common type of cutaneous tumor, but current drug treatments do not satisfy clinical practice requirements. At present, mitochondrial uncoupling is an effective antitumor treatment. Triclosan, a common antimicrobial, also acts as a mitochondrial uncoupler. The aims of the present study were to investigate the effects of triclosan on melanoma cells and the underlying mechanisms. Mitochondrial membrane potential (MMP), mitochondrial morphology, mitochondrial reactive oxygen species (mito-ROS), intracellular superoxide anion and [Ca 2+ ] i were measured using confocal microscopy. It was found that triclosan application was associated with decreased A375 cell viability in a dose-and time-dependent manner and these effects may have cell specificity. Furthermore, triclosan induced MMP depolarization, ATP content decrease, mito-ROS and [Ca 2+ ] i level increases, excessive mitochondrial fission, AMP-activated protein kinase (AMPK) activation and STAT3 inhibition. Moreover, these aforementioned effects were reversed by acetylcysteine treatment. Triclosan acute treatment also induced mitochondrial swelling, which was reversed after AMPK-knockdown associated with [Ca 2+ ] i overload. Cell death was caused by STAT3 inhibition but not AMPK activation. Moreover, triclosan induced autophagy via the ROS/AMPK/p62/microtubule-associated protein 1A/1B-light chain 3 (LC3) signaling pathway, which may serve a role in feedback protection. Collectively, the present results suggested that triclosan increased mito-ROS production in melanoma cells, following induced cell death via the STAT3/Bcl-2 pathway and autophagy via the AMPK/p62/LC3 pathway.

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IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway

Cited by 21 publications

References 50 publications

Ginsenoside Rh1 Prevents Migration and Invasion through Mitochondrial ROS-Mediated Inhibition of STAT3/NF-κB Signaling in MDA-MB-231 Cells

Ginsenoside Rh1 Prevents Migration and Invasion through Mitochondrial ROS-Mediated Inhibition of STAT3/NF-κB Signaling in MDA-MB-231 Cells

Potential Clinical Value of 5-Hydroxytryptamine Receptor 3C as a Prognostic Biomarker for Lung Cancer

Triclosan induces ROS‑dependent cell death and autophagy in A375 melanoma cells

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