Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Molecular biology of the cell (Impact Factor: 4.47). 04/2008; 19(3):797-806. DOI: 10.1091/mbc.E07-10-1092
Source: PubMed


Autophagy has been proposed to promote cell death during lumen formation in three-dimensional mammary epithelial acini because numerous autophagic vacuoles are observed in the dying central cells during morphogenesis. Because these central cells die due to extracellular matrix (ECM) deprivation (anoikis), we have directly interrogated how matrix detachment regulates autophagy. Detachment induces autophagy in both nontumorigenic epithelial lines and in primary epithelial cells. RNA interference-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis, and reduces clonogenic recovery after anoikis. Remarkably, matrix-detached cells still exhibit autophagy when apoptosis is blocked by Bcl-2 overexpression, and ATG depletion reduces the clonogenic survival of Bcl-2-expressing cells after detachment. Finally, stable reduction of ATG5 or ATG7 in MCF-10A acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling, even when combined with apoptotic inhibition mediated by Bcl-2 overexpression. Thus, autophagy promotes epithelial cell survival during anoikis, including detached cells harboring antiapoptotic lesions.

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    • "Autophagy mediated cell death is different from autophagy mediated cell survival (Marino et al., 2014). Induction of autophagy generally prevents apoptosis (Fung et al., 2008; Lum et al., 2005). However, persistent or excessive autophagy can promote cell death through induction of apoptosis (Jain et al., 2013; Shen and Codogno, Fig. 7. Effect of T-12 on autophagy-mediated cell death in MDA-MB-231 and MCF-7 cells. "
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    ABSTRACT: Autophagy is considered as an important cell death mechanism that closely interacts with other common cell death programs like apoptosis. Critical role of autophagy in cell death makes it a promising, yet challenging therapeutic target for cancer. We identified a series of 1,2,3 triazole analogues having significant breast cancer inhibition property. Therefore, we attempted to study whether autophagy and apoptosis were involved in the process of cancer cell inhibition. The lead molecule, 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4-chlorophenyl)ethanol (T-12) induced significant cell cycle arrest, mitochondrial membrane depolarization, apoptosis and autophagy in MCF-7 and MDA-MB-231 cells. T-12 increased reactive oxygen species and its inhibition by N-acetyl-L-cysteine protected breast cancer cells from autophagy and apoptosis. Autophagy inhibitor, 3-methyladenine abolished T-12 induced apoptosis, mitochondrial membrane depolarization and reactive oxygen species generation. This suggested that T-12 induced autophagy facilitated cell death rather than cell survival. Pan-caspase inhibition did not abrogate T-12 induced autophagy, suggesting that autophagy precedes apoptosis. In addition, T-12 inhibited cell survival pathway signaling proteins, Akt, mTOR and Erk1/2. T-12 also induced significant regression of tumor with oral dose of as low as 10mg/kg bodyweight in rat mammary tumor model without any apparent toxicity. In presence of reactive oxygen species inhibitor (N-acetyl-L-cysteine) and autophagy inhibitor (chloroquine), T-12 induced tumor regression was significantly decreased. In conclusion, T-12 is a potent inducer of autophagy-dependent apoptosis in breast cancer cells both in vitro and in vivo and can serve as an important lead in development of new anti-tumor therapy. Copyright © 2015. Published by Elsevier Ltd.
    The international journal of biochemistry & cell biology 06/2015; 65. DOI:10.1016/j.biocel.2015.06.016 · 4.05 Impact Factor
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    • "Recently, several groups have shown that matrix detachment that can occur during solid tumor growth and metastasis, can also activate AMPK (Jeon et al. 2012; Fung et al. 2008; Ng et al. 2012; Hindupur et al. 2014). Matrix detachment has been reported to inhibit glucose uptake and glycolysis, thereby inducing energetic stress (Schafer et al. 2009), which suggests that LKB1 may play a major role in AMPK activation in such cases. "
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    ABSTRACT: 5′-AMP-activated protein kinase (AMPK) plays a pivotal role in maintaining energy and redox homeostasis under various metabolic stress conditions. Metabolic adaptation, which can be triggered by the activation of AMPK during metabolic stress, is the critical process for cell survival through the maintenance of ATP and NADPH levels. The importance of such regulation of fundamental process poses the AMPK signaling pathway in one of the most attractive therapeutic targets in many pathologies such as diabetes and cancer. In cancer, however, accumulating data suggest that the role of AMPK would not be simply defined as anti- or pro-tumorigenic, but it seems to have two faces like a double-edged sword. Importantly, recent studies showed that the anti-tumorigenic effects of many ‘indirect’ AMPK activators such as anti-diabetic biguanides are not dependent on AMPK; rather the activation of AMPK induces the resistance to their cytotoxic effects, emphasizing the pro-tumorigenic effect of AMPK. In this review, we summarize and discuss recent findings suggesting the two faces of AMPK in cancer, and discuss how we can exploit this unique feature of AMPK for novel therapeutic intervention.
    Archives of Pharmacal Research 01/2015; 38(3). DOI:10.1007/s12272-015-0549-z · 2.05 Impact Factor
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    • "Exfoliation typically induces anoikis, rather than apoptosis, which is a form of programmed cell death induced by anchorage-dependent cells detaching from the surrounding extracellular matrix. Detachment also induces autophagy, which is a survival mechanism to loss of nutrients [51]. The exfoliated cells enter into a quiescent state and appear to maintain viability for differing lengths of time depending on the sources of cells. "
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    ABSTRACT: The early postnatal period is a critical window for intestinal and immune maturation. Intestinal development and microbiome diversity and composition differ between breast- (BF) and formula-fed (FF) infants. Mechanistic examination into host–microbe relationships in healthy infants has been hindered by ethical constraints surrounding tissue biopsies. Thus, a statistically rigorous analytical framework to simultaneously examine both host and microbial responses to dietary/environmental factors using exfoliated intestinal epithelial cells was developed. Differential expression of ∼1200 genes, including genes regulating intestinal proliferation, differentiation and barrier function, was observed between BF and FF term infants. Canonical correlation analysis uncovered a relationship between microbiome virulence genes and host immunity and defense genes. Lastly, exfoliated cells from preterm and term infants were compared. Pathways associated with immune cell function and inflammation were up-regulated in preterm, whereas cell growth-related genes were up-regulated in the term infants. Thus, coordinate measurement of the transcriptomes of exfoliated epithelial cells and microbiome allows inquiry into mutualistic host–microbe interactions in the infant, which can be used to prospectively study gut development or, retrospectively, to identify potential triggers of disease in banked samples.
    FEBS Letters 11/2014; 588(22). DOI:10.1016/j.febslet.2014.07.008 · 3.17 Impact Factor
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