Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress

Ullman, Erica; Fan, Yun; Stawowczyk, Marcin; Hm, Chen; Yue, Zhenggang; Zong, W-X

doi:10.1038/sj.cdd.4402234

Cited by 144 publications

(133 citation statements)

References 20 publications

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“…Recent studies have suggested that induction of autophagy may be an effective therapeutic approach for apoptosis-resistant cancer cells (Ullman et al, 2008). In the present study, we demonstrated that the mTOR inhibitor rapamycin induced autophagy in Ras-NIH3T3/Mdr cells and that this biological process mediated the growth inhibitory effect of rapamycin.…”

Section: Discussionsupporting

confidence: 69%

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Eum

Lee

2011

Molecules and Cells

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Section: Discussionsupporting

confidence: 69%

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Eum

Lee

2011

Molecules and Cells

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“…The epilogue of apoptotic and autophagic cell death could be the accidental death known as necrosis. Moreover, in apoptosis-deficient cells, autophagy promotes necrosis (38). Therefore, the observed late LDH release after GIT-27NO treatment is the consequence of both types of programmed cell death rather then primary necrosis.…”

Section: Discussionmentioning

confidence: 99%

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić

Mijatović

Harhaji

et al. 2008

Molecular Cancer Therapeutics

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Preclinical studies have shown that nitric oxide (NO) -donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NOdeprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatinresistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.

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“…In cancer cells, autophagy inhibited starvation-induced apoptotic death (Boya et al, 2005) and also necrotic cell death, especially in conjunction with a block in apoptosis (Jin and White, 2007;Karantza-Wadsworth et al, 2007). Conversely, autophagy was required for necrotic death of neuronal cells in C. elegans (Samara et al, 2008), for stress-mediated necrosis in apoptosis-deficient BaxÀ/ÀBakÀ/À mouse embryonic fibroblasts (MEFs) (Shimizu et al, 2004;Ullman et al, 2008) and loss of autophagy through deletion of Atg7 rescued neurons from death after hypoxia/reperfusion (Koike et al, 2008). Resolving the relationship between autophagy and apoptosis is especially complex, as both are induced by similar stimuli and impact on each other's functions (Maiuri et al, 2007c;Levine et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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The binding of Bcl-2 to Beclin-1 reduces Beclin-1's capacity to induce autophagy. Here, we have tested whether the interaction is reciprocated by loss of Bcl-2's anti-apoptotic function. We targeted Bcl-2 to mitochondria or endoplasmic reticulum (ER) and induced apoptosis using several apoptotic stimuli that initiate ER and/or mitochondrial signaling pathways (UV radiation, TNF and cycloheximide, staurosporine, thapsigargin and tunicamycin). When Beclin-1 and Bcl-2 were expressed together in HeLa cells, Beclin-1 (but not Beclin-1 lacking the Bcl-2-binding domain) followed Bcl-2 to the appropriate organelle with complete or near-complete overlap (comprising 60 and 30% of cells, respectively). The interaction between Beclin-1 and Bcl-2 was verified by immunoprecipitation, and a membrane-proximate localization of Beclin-1 was shown by immunoelectron microscopy. Apoptosis was followed by measuring changes in nuclear morphology, caspase-3 activity, poly-ADP-ribose polymerase cleavage or punctation of mRFP-Bax on mitochondria. Binding of Beclin-1 to Bcl-2 did not modify apoptosis irrespective of Bcl-2 concentration, location or apoptotic stimulus. A similar result was obtained in Atg5À/À cells that are autophagy-deficient, arguing against compensation for the loss of protection by Bcl-2 by autophagy-mediated survival induced by Beclin-1. Hence, although Beclin-1 contains a BH3-only motif typical of pro-apoptotic proteins, it is a negligible modulator of Bcl-2's anti-apoptotic function.

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Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress

Cited by 144 publications

References 20 publications

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

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