Arecoline downregulates levels of p21 and p27 through the reactive oxygen species/m<scp>TOR</scp> complex 1 pathway and may contribute to oral squamous cell carcinoma

Ji, Wen-Tsai; Yang, Sheng-Ru; Chen, Jeff Yi‐Fu; Cheng, Ye; Lee, Ying‐Ray; Chiang, Ming-Ko; Chen, Hau-Ren

doi:10.1111/j.1349-7006.2012.02294.x

Cited by 42 publications

(37 citation statements)

References 61 publications

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“…ROS reportedly functions in cancer drug resistance [22]. ANE can induce the generation of ROS in both normal and cancerous epithelium cells [23,29,30]. ROS is also associated with autophagy.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

Huang

Shao

et al. 2017

IJMS

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Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 μg). Cisplatin toxicity (IC50, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 μg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

Huang

Shao

et al. 2017

IJMS

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“…Interplay between ROS and mTOR signaling is complicated, since ROS as a signaling molecule plays both activating and inhibitory roles. Increasing evidence suggests that mTORC1 is a critical ROS mediator [39–41]. Recently, Sorafenib-mediated breast cancer inhibition was shown to be dependent on mTORC1 inhibition and accompanied by mitochondrial membrane depolarization and dramatic ROS increase [42].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells

et al. 2015

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Elevated oxidative stress in cancer cells contributes to hyperactive proliferation and enhanced survival, which can be exploited using agents that increase reactive oxygen species (ROS) beyond a threshold level. Here we show that melanoma cells exhibit an oxidative stress phenotype compared with normal melanocytes, as evidenced by increased total cellular ROS, KEAP1/NRF2 pathway activity, protein damage, and elevated oxidized glutathione. Our overall objective was to test whether augmenting this high oxidative stress level in melanoma cells would inhibit their dependence on oncogenic PI3K/AKT/mTOR-mediated survival. We report that NexrutineR augmented the constitutively elevated oxidative stress markers in melanoma cells, which was abrogated by N-acetyl cysteine (NAC) pre-treatment. NexrutineR disrupted growth homeostasis by inhibiting proliferation, survival, and colony formation in melanoma cells without affecting melanocyte cell viability. Increased oxidative stress in melanoma cells inhibited PI3K/AKT/mTOR pathway through disruption of mTORC1 formation and phosphorylation of downstream targets p70S6K, 4EBP1 and rpS6. NAC pre-treatment reversed inhibition of mTORC1 targets, demonstrating a ROS-dependent mechanism. Overall, our results illustrate the importance of disruption of the intrinsically high oxidative stress in melanoma cells to selectively inhibit their survival mediated by PI3K/AKT/mTOR.

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“…Those results indicate that p18 protein somehow involves in controlling autophagy at the starved condition through a functional connection with p27 kip1 . The p27 kip1 has been suggested in a critical role in mTOR or AMPK signal pathways (Larrea et al, 2009;Lacher et al, 2010;Ji et al, 2012). Particularly, it triggers to induce autophagy by sensing the intracellular energy level via LKB/AMPK signaling.…”

Section: Discussionmentioning

confidence: 99%

Depletion of p18/LAMTOR1 promotes cell survival via activation of p27^kip1‐dependent autophagy under starvation

Zada

Noh

Baek

et al. 2015

Cell Biology International

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The MAPK and mTOR signal pathways in endosomes or lysosomes play a crucial role in cell survival and death. They are also closely associated with autophagy, a catabolic process highly regulated under various cellular stress or nutrient deprivation. Recently we have isolated a protein, named p18/LAMTOR1, that specifically regulates the ERK or mTOR pathway in lysosomes. p18/LAMTOR1 also interacts with p27(kip1) . Here we examined how p18/LAMTOR1 plays a role in autophagy under nutrient deprivation. The p18(+/+) MEF cells were more susceptible to cell death under starvation or in the presence of AICAR in comparison with p18(-/-) MEF cells. Cleavage of caspase-3 was increased in p18(+/+) MEF cells under starvation, and phosphorylation at the threonine 198 of p27(kip1) was highly elevated in starved p18(-/-) MEF cells. Furthermore, LC3-II formation and other autophagy-associated proteins were largely increased in p18-deficient cells, and suppression of p27(kip1) expression in p18(-/-) MEF cells mitigated starvation-induced cell death. These data suggest that ablation of p18/LAMTOR1 suppresses starvation-induced cell death by stimulating autophagy through modulation of p27(kip1) activity.

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Arecoline downregulates levels of p21 and p27 through the reactive oxygen species/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma

Cited by 42 publications

References 61 publications

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells

Depletion of p18/LAMTOR1 promotes cell survival via activation of p27^kip1‐dependent autophagy under starvation

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Arecoline downregulates levels of p21 and p27 through the reactive oxygen species/mTOR complex 1 pathway and may contribute to oral squamous cell carcinoma

Cited by 42 publications

References 61 publications

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells

Depletion of p18/LAMTOR1 promotes cell survival via activation of p27kip1‐dependent autophagy under starvation

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Depletion of p18/LAMTOR1 promotes cell survival via activation of p27^kip1‐dependent autophagy under starvation