Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

Yu, Hui; Lin, Chen-Si; Tai, Wei-Tien; Liu, Chun Yu; Shiau, Chung Wai; Chen, Kuen Feng

doi:10.1074/jbc.m112.446385

Cited by 84 publications

(71 citation statements)

References 47 publications

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“…In contrast to apoptosis, autophagy is dependent on the presence of autophagosomes and autolysosomes, as well as an intact nucleus [50]. In contrast to apoptosis, autophagy is dependent on the presence of autophagosomes and autolysosomes, as well as an intact nucleus [50].…”

Section: Discussionmentioning

confidence: 95%

Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells

et al. 2014

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We found that artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells. ART arrested the cell cycle in the G2/M phase, which was accompanied by an upregulation of p21. ART upregulated the expression of Beclin1, an initiator of autophagy (type II programmed cell death). In addition, ART stimulated the aggregation of LC3, which is considered to be a marker of autophagosome formation. We further verified the transformation of LC3 from type I into type II. 3-MA, a classical autophagy inhibitor, attenuated ART-induced autophagosome formation, cell growth repression, G2/M arrest, and p21 upregulation. Autophagy induction and p21 upregulation were also repressed by knockdown of Beclin1. Furthermore, ART sensitized breast cancer cells to the chemotherapeutic agent epirubicin through an autophagy-dependent cascade. Our study showed that ART induced autophagy in breast cancer cells and indicated that the anticancer effects of ART were exerted through an autophagy pathway. Moreover, ART sensitized breast cancer cells to epirubicin chemotherapy. Our results provide a basis for further development of ART as a novel therapeutic agent for the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 95%

Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells

et al. 2014

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“…Nilotinib also elevated AMPK phosphorylation and blocked protein phosphatase PP2A. Inducing PP2A decreased AMPK-mediated nilotinib activation and subsequent autophagy (Yu et al 2013). …”

Section: Ampk As a Target To Control Cancer Growth And Treatment Sensmentioning

confidence: 96%

“…It was shown that CrT1-induced AMPK blocked the mTOR/(p70)S6K pathway (Sul et al 2013). The actions of nilotinib on hepatocellular carcinoma (HCC) were investigated (Yu et al 2013). Nilotinib is an oral tyrosine kinase inhibitor approved for treatment of chronic myelogenous leukemia.…”

Section: Ampk As a Target To Control Cancer Growth And Treatment Sensmentioning

confidence: 99%

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

Elmacı

Altinöz²

2016

Biochem Genet

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Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

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“…We have shown that TKIs induce autophagy and lead to protein degradation in mice and in vitro (Lonskaya, Hebron, Desforges, Franjie, & Moussa, 2013; Lonskaya, Hebron, Desforges, Schachter, & Moussa, 2014; Chen, et al, 2014). Tyrosine kinase inhibition has been shown to increase autophagy in other cell types and animal models (Bellodi, et al, 2009; Shaker, Ghani, Shiha, Ibrahim, & Mehal, 2013; Yu, et al, 2013; Mahul-Mellier, et al, 2014). TKIs, including the FDA-approved chronic myelogenous leukemia drugs Nilotinib and Bosutinib, reverse cell death in transgenic TDP-43 mice (Chen, et al, 2014) by differentially modifying TDP-43.…”

Section: Autophagymentioning

confidence: 99%

TDP-43 in the spectrum of MND-FTLD pathologies

Heyburn

Moussa

2017

Molecular and Cellular Neuroscience

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The relationship between RNA-binding proteins, particularly TAR DNA binding protein 43 (TDP-43), and neurodegeneration is an important area of research. TDP-43 is involved in so many cellular processes that perturbation of protein homeostasis can lead to countless downstream effects. Understanding what leads to this disease-related protein imbalance and the resulting cellular and molecular effects will help to develop targets for disease intervention, whether it be prevention of protein accumulation, or addressing a secondary effect of protein accumulation. Here we review the current literature of TDP-43 and TDP-43 pathologies, the effects of TDP-43 overexpression and disruption of synaptic proteins through its binding of messenger RNA, leading to synaptic dysfunction. This review highlights some of the still-limited knowledge of the protein TDP-43 and how it can contribute to disease.

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Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

Cited by 84 publications

References 47 publications

Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells

Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

TDP-43 in the spectrum of MND-FTLD pathologies

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