Article

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: 5.98). 04/2008; 19(3):797-806. DOI: 10.1091/mbc.E07-10-1092
Source: PubMed

ABSTRACT 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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    • "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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    • "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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    • "Autophagy can increase oxidative stress, thereby promoting genome instability and malignant transformation [15] [16] [17] [18], and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress [16]. Additionally, it has been suggested that metastatic cancer cells may escape from anoikis (process of apoptosis induced by lack of correct cell-extracellular matrix attachment) via the induction of autophagy [19] [20]. Current BC therapy depends on the type and stage of the BC and traditionally consists of a multivariate approach including surgery, hormone therapy, systemic chemotherapy, radiotherapy, and molecular targeted therapy [2] [9]. "
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