Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells

Zhang, Rong; Li, Guobing�; Zhang, Qian; Tang, Qin; Huang, Jingbin�; Hu, Changpeng�; Liu, Yali; Wang, Qing; Liu, Wuyi; Gao, Ning; Zhou, Shiwen

doi:10.1038/s41419-018-0641-7

Cited by 62 publications

(54 citation statements)

References 53 publications

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“…Several researches have demonstrated that the activation of ROCK1 could activate PTEN, further inactivate PI3K/AKT, subsequently leading in turn to GSK‐3β dephosphorylation and mPTP opening, and we found that GAS5 could positively regulate ROCK1. Therefore, whether GAS5 regulates PTEN/PI3K/AKT/GSK‐3β/mPTP signal axis was further explored.…”

Section: Resultsmentioning

confidence: 58%

“…For instance, once mPTP opens, cytochrome c will be driven from the mitochondria into the cytoplasm, then caspases cascades are activated, and ultimately cell apoptosis will occur . GSK‐3β, a key upstream regulator of mPTP opening, is typically regulated by the PI3K/AKT‐mediated phosphorylation . mPTP opening will decrease, once GSK‐3β at Ser9 cite is phosphorylated .…”

Section: Discussionmentioning

confidence: 99%

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Down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR‐335/ROCK1/AKT/GSK‐3β axis

Zhang

Bao

et al. 2019

J Cellular Molecular Medi

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Growth arrest‐specific transcript 5 (GAS5), along non‐coding RNA (LncRNA), is highly expressed in hypoxia/reoxygenation (H/R)‐cardiomyocytes and promotes H/R‐induced apoptosis. In this study, we determined whether down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion (I/R) injury and further explored its mechanism. GAS5 expression in cardiomyocytes and rats was knockdown by transfected or injected with GAS5‐specific small interfering RNA or adeno‐associated virus delivering small hairpin RNAs, respectively. The effects of GAS5 knockdown on myocardial I/R injury were detected by CCK‐8, myocardial enzyme test, flow cytometry, TTC and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. qRT‐PCR and luciferase reporter assay were carried out to analyse the relationship between GAS5 and miR‐335. The regulation of GAS5 on Rho‐associated protein kinase 1 (ROCK1) expression, the activation of PI3K/AKT/GSK‐3β pathway and mitochondrial permeability transition pore (mPTP) opening was further evaluated. The results indicated that GAS5 knockdown enhanced the viability, decreased apoptosis and reduced the levels of lactate dehydrogenase and creatine kinase‐MB in H/R‐treatment cardiomyocytes. Meanwhile, down‐regulation of GAS5 limited myocardial infarct size and reduced apoptosis in I/R‐heart. GAS5 was found to bind to miR‐335 and displayed a reciprocal inhibition between them. Furthermore, GAS5 knockdown repressed ROCK1 expression, activated PI3K/AKT, thereby leading to inhibition of GSK‐3β and mPTP opening. These suppressions were abrogated by miR‐335 inhibitor treatment. Taken together, our results demonstrated that down‐regulation of GAS5 ameliorates myocardial I/R injury via the miR‐335/ROCK1/AKT/GSK‐3β axis. Our findings suggested that GAS5 may be a new therapeutic target for the prevention of myocardial I/R injury.

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Section: Resultsmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR‐335/ROCK1/AKT/GSK‐3β axis

Zhang

Bao

et al. 2019

J Cellular Molecular Medi

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“…At the molecular level, ROCK1 promotes mitochondrial dysfunction and mitochondria-related apoptosis through the PTEN pathway and PI3K/Akt pathway in human leukemia cells. 50 In this study, we can be certain that miR-31 is the upstream effector of ROCK1/F-actin axis, and inhibiting the ROCK1/F-actin pathway abolishes the beneficial effects of miR-31 on viability, mitochondrial function, proliferation, and movement in liver cancer HepG2 cells. However, the targets of miR-31 are not clearly described in this study.…”

Section: Discussionmentioning

confidence: 78%

<p>miR-31 Modulates Liver Cancer HepG2 Cell Apoptosis and Invasion via ROCK1/F-Actin Pathways</p>

Zhang¹,

Xu²,

Yang³

2020

OTT

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Purpose: Liver cancer is one of the most common malignant tumor in the world. miR-31 is downregulated in liver cancer and associated with tumor growth and metastasis. However, the underlying mechanism remains unclear. Methods: Cellular apoptosis was detected via MTT, TUNEL assay, LDH release and Annexin V/PI flow-cytometry analysis. Cellular migration and invasion were measured by the Transwell chamber assay. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining and mPTP opening assessment. The mitophagy activity was examined via Western blots. Results: In the present study, our results confirm that miR-31 promotes apoptosis and inhibits proliferation and metastasis in liver cancer HepG2 cells. In vitro, miR-31 promotes HepG2 cell apoptosis through the mitochondrial pathway as indicated by mitochondrial potential reduction, increased mPTP opening time, cty-c release and imbalance of pro-and anti-apoptotic proteins. Furthermore, miR-31 reduces the energy generation by inhibiting mitochondrial respiratory function. At last, it is demonstrated that miR-31 triggers the mitochondrial damage via ROCK1/F-actin pathway. Inhibiting the ROCK1/F-actin pathway abolishes the effects of miR-31 mimic on mitochondrial injury, apoptosis, proliferation arrest and migration inhibition. Conclusion: Our results reveal that miR-31 can inhibit HepG2 cell survival and metastasis by activating the ROCK1/F-actin pathway.

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“…Growing evidence has demonstrated that active Akt promotes survival of cardiomyocytes in vitro and protects against MIRI [18]. Gsk-3β, a crucial downstream molecule of PI3K/Akt signal pathway, typically regulated mPTP opening by PI3K/Akt-mediated phosphorylation [19]. Several studies have reported that ischemic preconditioning [20] or postconditioning [21] could prevent MIRI through activation of PI3K-Akt-Gsk-3β pathway and subsequent inhibition of mPTP opening.…”

Section: Discussionmentioning

confidence: 99%

Sappanone A alleviates hypoxia/reoxygenation-induced cardiomyocytes injury through inhibition of mitochondrial apoptosis and activation of PI3K–Akt–Gsk-3β pathway

Shi¹,

Gao²,

Ji³

et al. 2020

Bioscience Reports

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Myocardial ischemia reperfusion injury (MIRI) is a complex pathophysiological process involved with the activation of oxidative stress, inflammation and apoptosis. Sappanone A (SA), a homoisoflavanone isolated from the heartwood of Caesalpinia sappan L., could exhibit antioxidant, anti-inflammatory and anti-apoptotic activities. Therefore, we assumed that SA has a potential use for preventing against MIRI. The present study aimed to investigate the effect of SA treatment on MIRI and its mechanism. Cardiomyocytes (H9c2 cells) were treated with SA for 1 h, followed by 6 h of hypoxia/3 h of reoxygenation. Cell viability assay was detected by CCK-8 assay. Apoptosis was measured by flow cytometry and Hoechst staining. Mitochondrial permeability transition pore (mPTP) opening and mitochondrial transmembrane potential ( ψm) were measured by spectrophotometry and JC-1 staining. The changes of mitochondrial apoptosis-related proteins and PI3K-Akt-Gsk-3β signaling pathway were evaluated by Western blotting. The results showed that SA pretreatment enhanced the cell viability and decreased the activity of myocardial enzyme in a dose-dependent manner. Moreover, SA pretreatment significantly inhibited apoptosis, blocked mPTP opening, suppressed the release of ψm, prevented the cytochrome c releasing from mitochondria into cytoplasm, and repressed the cleavage of caspase-9 and caspase-3. Furthermore, SA pretreatment increased the phosphorylation levels of Akt and Gsk-3β but not of Stat-3. Meanwhile, the protective effect of SA was abrogated by PI3K inhibitor (LY294002). In conclusion, our results demonstrate that SA could prevent hypoxia/reoxygenation-induced cardiomyocytes injury through inhibition of mitochondrial apoptosis and activation of PI3K-Akt-Gsk-3β pathway. Thus, SA may have a potential use for the prevention of MIRI.

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Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells

Cited by 62 publications

References 53 publications

Down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR‐335/ROCK1/AKT/GSK‐3β axis

Down‐regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR‐335/ROCK1/AKT/GSK‐3β axis

<p>miR-31 Modulates Liver Cancer HepG2 Cell Apoptosis and Invasion via ROCK1/F-Actin Pathways</p>

Sappanone A alleviates hypoxia/reoxygenation-induced cardiomyocytes injury through inhibition of mitochondrial apoptosis and activation of PI3K–Akt–Gsk-3β pathway

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