Molecular mechanism and regulation of autophagy1

Yang, Yaping; Liang, Zhong‐Qin; Z, Gu; Qin, Zheng‐Hong

doi:10.1111/j.1745-7254.2005.00235.x

Cited by 187 publications

(175 citation statements)

References 127 publications

(138 reference statements)

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“…26 When MDA-MB231 cells were coincubated with 8.45 μM JAHA and 1 nm rapamycin, by analogy with BHT treatment, we found that also this cotreatment was capable of reversing the JAHAtriggered decrease in cell number (Figure 9), thereby revealing autophagy inhibition as a further aspect, supplementary to early ROS production, involved in the cytotoxic effect exerted by the HDACi under study on MDA-MB231 breast tumor cells.…”

Section: ■ Resultsmentioning

confidence: 99%

Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells

Librizzi

Longo

Chiarelli

et al. 2012

Chem. Res. Toxicol.

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The histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives may be obtained by three-dimensional manipulation of SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA [Spencer, et al. (2011) ACS Med. Chem. Lett. 2, 358−362]. These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple-negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC 50 of 8.45 μM at 72 h of treatment. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G 2 /M transition and in an early reactive oxygen species production followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short-(5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi. Although caution must be exercised in extrapolation of in vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of "aggressive" breast carcinoma, thus prompting us to get more insight into the molecular basis of its antibreast cancer activity.

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Section: ■ Resultsmentioning

confidence: 99%

Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells

Librizzi

Longo

Chiarelli

et al. 2012

Chem. Res. Toxicol.

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“…Autophagy starts with the formation of an autophagosome, enclosed within a double membrane that engulfs part of cytoplasm. The formation of autophagosome depends upon Atg proteins [34]. Autophagy can be stimulated by various stresses, including nutrient depletion or hypoxia.…”

Section: Discussionmentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

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Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

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“…Although autophagy and autophagy-related processes are dynamic, they can be broken down into several discrete steps for the purpose of discussion: (1) induction, (2) autophagosome formation, (3) autophagolysosome formation, and (4) delivery and degradation of the autophagic body [1] . Autophagy is induced as a response to both extracellular stress conditions (nutrient deprivation, hypoxia, and oxidative stress) and intracellular stress conditions (endoplasmic reticulum stress, accumulation of damaged organelles, and aggregation of proteins).…”

Section: Mechanisms and Pharmacologic Targeting Of Autophagymentioning

confidence: 99%

“…Autophagy is a universal, dynamic process that takes place in all eukaryotic cells. There are three primary forms of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy [1] . Of these classifications, macroautophagy, herein referred to as autophagy, is the major form of autophagy and has been well characterized in recent years.…”

Section: Introductionmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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Molecular mechanism and regulation of autophagy1

Cited by 187 publications

References 127 publications

Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells

Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Application and interpretation of current autophagy inhibitors and activators

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