The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival

Kang, Rui; Tang, Daolin; Schapiro, Nicole E.; Livesey, Kristen M.; Farkas, Adam M.; Loughran, Patricia; Bierhaus, Angelika; Lotze, Michael T.; Zeh, Herbert J.

doi:10.1038/cdd.2009.149

Cited by 283 publications

(286 citation statements)

References 45 publications

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“…Moreover, RAGE sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival in vivo and in vitro. 54,55 In contrast, oxidized HMGB1 increases the cytotoxicity of these agents and induces apoptosis via the mitochondrial pathway. We propose a new function for HMGB1 within the tumor microenvironment: as a regulator of cell death and survival, suggesting that HMGB1 has an important functional role in cross-regulating apoptosis and autophagy.…”

Section: Other Beclin 1-binding Proteins In Autophagymentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

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Section: Other Beclin 1-binding Proteins In Autophagymentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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“…Moreover, HMGB1 promotes stem cell migration and proliferation, and recruitment of acute inflammatory cells including macrophages and neutrophils (Lotze and Tracey, 2005;Tang et al, 2010d). One of the HMGB1 receptors, receptor for advanced glycation end products, has been implicated in tumorigenesis, metastasis, apoptosis and autophagy (Taguchi et al, 2000;Gebhardt et al, 2008;Kang et al, 2010). Thus DAMPs and the associated DAMP receptors within the tumor microenvironment are an attractive target for improving cancer therapy and possibly, for cancer prevention (Figure 1e).…”

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Apoptosis promotes early tumorigenesis

et al. 2010

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“…10 Moreover, receptor for advanced glycation end products and HMGB1 sustain autophagy and limits apoptosis, promoting pancreatic and colon tumor cell survival. [11][12][13] We have previously demonstrated that endogenous HMGB1 is a negative regulator of apoptosis in leukemia cells. 14,15 Overexpression of HMGB1 by gene transfection rendered leukemia cells resistant to apoptosis; whereas suppression of HMGB1 expression by RNA interference increased the sensitivity of leukemia cells to chemotherapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

et al. 2010

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Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3-II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia.

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The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival

Cited by 283 publications

References 45 publications

The Beclin 1 network regulates autophagy and apoptosis

The Beclin 1 network regulates autophagy and apoptosis

Apoptosis promotes early tumorigenesis

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

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