Autophagy—from molecular mechanisms to clinical relevance

Lippai, Mónika; Szatmári, Zsuzsanna

doi:10.1007/s10565-016-9374-5

Cited by 67 publications

(58 citation statements)

References 229 publications

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“…Autophagy is a complex process, fine-tuned by several environmental signals involved in nutrient signaling, growth factor status, energy sensing, hypoxia, oxidative and ER stress, and infection [36]. AMPK and mTOR signaling pathways have been revealed as the central checkpoints in the regulation of autophagy [37].…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma

Wang

Liu

Hong

et al. 2017

J Exp Clin Cancer Res

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BackgroundGlioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM.MethodsCell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo.ResultsIbrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo.ConclusionsOur results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0549-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma

Wang

Liu

Hong

et al. 2017

J Exp Clin Cancer Res

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“…Recently, autophagy has been shown to be modulated and to participate in the pathogenesis of human diseases, such as DM, neurodegenerative diseases, aging, pathogen infection diseases, vascular disease, pulmonary disease and cancer (Fig. 2) [13, 63–68]. Dr. Yoshinori Ohsumi discovered autophagy-related genes (ATGs) using a genetic screening approach in Saccharomyces cerevisiae and awarded the 2016 Nobel Prize in Physiology or Medicine for his remarkable contribution to autophagy research [1, 4, 69–71].…”

Section: Programmed Cell Death (Pcd)mentioning

confidence: 99%

“…1) [6–11]. In addition, autophagy, a catabolic process, degrades cellular components and damaged organelles [12, 13]. Recently, autophagic machinery is involved in the pathophysiology of type 2 diabetes mellitus (T2DM) disease, and it regulates normal function of pancreatic beta cells.…”

Section: Introductionmentioning

confidence: 99%

Autophagy and its link to type II diabetes mellitus

Yang¹,

Lu²,

Kuo³

et al. 2017

BioMedicine

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Autophagy, a double-edged sword for cell survival, is the research object on 2016 Nobel Prize in Physiology or Medicine. Autophagy is a molecular mechanism for maintaining cellular physiology and promoting survival. Defects in autophagy lead to the etiology of many diseases, including diabetes mellitus (DM), cancer, neurodegeneration, infection disease and aging. DM is a metabolic and chronic disorder and has a higher prevalence in the world as well as in Taiwan. The character of diabetes mellitus is hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and failure of producing insulin on pancreatic beta cells. In T2DM, autophagy is not only providing nutrients to maintain cellular energy during fasting, but also removes damaged organelles, lipids and miss-folded proteins. In addition, autophagy plays an important role in pancreatic beta cell dysfunction and insulin resistance. In this review, we summarize the roles of autophagy in T2DM.

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“…More recently, a role was recognized for lysosomes as important players for the clearance of endogenous material. This process, called autophagy, was demonstrated to be genetically determined and fundamental for maintaining the homeostasis of the cell, since it allows to degrade or recycle cellular components thus providing new material to renew the cell or energy in case of starvation [62][63][64].…”

Section: Lysosome and Autophagy Impairmentmentioning

confidence: 99%

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

Piscianz

Cuzzoni

Sharma

et al. 2018

CMC

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The story of antimalarials as antinflammatory drugs dates back few centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, the molecular mechanisms of action have been partly clarified.The inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway deputed to the sensing of nucleic acid and to the production of type 1 interferons. This pathway is a fundamental mechanism for host defence, since it is able to detect microbial DNA and RNA and induce the immune response that will lead to the production of interferons. Of note, genetic defects in disposal of nucleic acids lead to inappropriate activation of the cGAS-STING pathway and inflammation. These disorders, named type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials.We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and, likely multifactorial disorders characterised by interferon inflammation, such as systemic lupus erythematosus.

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Autophagy—from molecular mechanisms to clinical relevance

Cited by 67 publications

References 229 publications

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma

Autophagy and its link to type II diabetes mellitus

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs

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