Autophagy as a Stress-Response and Quality-Control Mechanism: Implications for Cell Injury and Human Disease

Murrow, Lyndsay; Debnath, Jayanta

doi:10.1146/annurev-pathol-020712-163918

Cited by 477 publications

(397 citation statements)

References 152 publications

(216 reference statements)

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“…This process serves as an essential cytoprotective response to pathologic stresses [29]. Accumulation of defective mitochondria triggers its selective degradation, process known as mitochondrial autophagy or mitophagy, maintaining a healthy population of these organelles [30,31].…”

Section: Discussionmentioning

confidence: 99%

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Rodilla

Korrodi‐Gregório

Hernando

et al. 2017

Biochemical Pharmacology

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Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with different mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favors cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as a novel antitumor drugs. Despite this, little is known about the implications of pH deregulation and homeostasis imbalance triggered by ionophores at the cellular level. In this work, we deeply analyze for the first time the anticancer effects of tambjamine analogues, a group of highly effective anion selective ionophores, at the cellular and molecular level. First, their effects on cell viability were determined in several lung cancer cell lines and patient-derived cancer stem cells, demonstrating their potent cytotoxic effects. Then, we have characterized the induced lysosomal deacidification, as well as, the massive cytoplasmic vacuolization observed after treatment with these compounds, which is consistent with mitochondrial swelling. Finally, the activation of several proteins involved in stress response, autophagy and apoptosis was also detected, although necrosis was the main mechanism of cell death induced.Altogether, these evidences suggest that tambjamine analogues provoke an imbalance in cellular ion homeostasis that triggers mitochondrial dysfunction and lysosomal deacidification leading to a potent cytotoxic effect through necrosis in lung cancer cell lines and cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Rodilla

Korrodi‐Gregório

Hernando

et al. 2017

Biochemical Pharmacology

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show abstract

“…Autophagy is an important quality-control mechanism in the human body that serves to degrade long-lived and damaged cytoplasmic organelles to generate new substrates for energy production. This is particularly important during periods of stress, starvation and infection and this homeostatic function protects against a wide variety of disorders, including liver disease (Levine andYuan 2006, Murrow andDebnath 2013). The autophagy process must be tightly regulated; too much or too little can be deleterious (Chen and Klionsky 2011).…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

Casey

Slattery

Cotter

et al. 2015

J of Inher Metab Disea

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Summary BackgroundRecessive LARS mutations were recently reported to cause a novel syndrome, Infantile Liver Failure Syndrome Type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management.

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“…18 Given that recent studies have demonstrated that oncogenic H-Ras or K-Ras promotes basal autophagy as a mechanism to promote tumor cell survival, [19][20][21][22] we assessed if EcdCRas promote cell survival under nutrient deprivation by elevating autophagy markers.…”

Section: Ecd Plus Ras Overexpression Induces Upregulation Of Autophagmentioning

confidence: 99%

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

et al. 2015

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Autophagy as a Stress-Response and Quality-Control Mechanism: Implications for Cell Injury and Human Disease

Cited by 477 publications

References 152 publications

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

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