A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells

Kar, Rekha; Singha, Prajjal K.; Venkatachalam, Manjeri A.; Saikumar, Pothana

doi:10.1038/onc.2009.118

Cited by 115 publications

(128 citation statements)

References 42 publications

(47 reference statements)

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“…2b) showed high similarity scores with the responses to well known UPR inducers and proteasome inhibitors such as, geldanamycin, 17-allylamino-geldanamycin, and MG-132 (29,42,43). Interestingly the highest similarity score was obtained for 15-⌬ prostaglandin J2 that is most recently been demonstrated to induce a paraptotic-like cell death (44), strikingly similar to that triggered by A0. Moreover, a microarray analysis, performed on cancer cells treated with a putative proteasome inhibitor (45), identified a set of 28 up-regulated genes, 21 of which were also up-regulated by A0.…”

Section: Discussionmentioning

confidence: 85%

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

120

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The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitinproteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2␣ phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2␣, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2␣ phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2␣ phosphorylation and the UPR.

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Section: Discussionmentioning

confidence: 85%

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

120

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“…It can serve as a safeguard mechanism by which, when sensing a stress resulting from a massive amount of misfolded proteins that cannot be resolved by autophagy flux, cells commit to die by apoptosis to maintain organismal homeostasis. Indeed, the proapoptotic function of LC3 has been recently reported (14,30). A number of cancers have been reported to have elevated levels of LC3 (39,57).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Degradation Induces Apoptosis through a Microtubule-Associated Protein 1 Light Chain 3-Mediated Activation of Caspase-8 at Intracellular Membranes

Pan

Ullman

Dou

et al. 2011

Molecular and Cellular Biology

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The accumulation of damaged or misfolded proteins, if unresolved, can lead to a detrimental consequence within cells termed proteotoxicity. Since cancerous cells often display elevated protein synthesis and byproduct disposal, inhibition of the protein degradation pathways is an emerging approach for cancer therapy. However, the molecular mechanism underlying proteotoxicity remains largely unclear. We show here that inhibition of proteasomal degradation results in an increased oligomerization and activation of caspase-8 on the cytosolic side of intracellular membranes. This enhanced caspase-8 oligomerization and activation are promoted through its interaction with the ubiquitin-binding protein SQSTM1/p62 and the microtubuleassociated protein light chain 3 (LC3), which are enriched at intracellular membranes in response to proteotoxic stress. Silencing LC3 by shRNA, or the LC3 mutants defective in membrane localization or p62 interaction fail to induce caspase-8 activation and apoptosis. Our results unveiled a previously unknown mechanism through which disruption of protein homeostasis induces caspase-8 oligomerization, activation, and apoptosis.

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“…AD cell models were seeded and cultured in 96-well plates at a density of 2x10 4 cells/ml in complete medium and incubated overnight. The cell viability was detected using an MTT assay (Sigma-Aldrich, St. Louis, MO, USA), as described previously (6). The MTT assay was performed at different time points, which included 24, 48 and 72 h.…”

Section: Methodsmentioning

confidence: 99%

Paraptosis triggers mitochondrial pathway-mediated apoptosis in Alzheimer's disease

Jia¹,

Wang²,

Zhang³

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. In previous years, increasing evidence has indicated that paraptosis and mitochondrial-mediated apoptosis may be associated with Alzheimer's disease (AD). However, the association between paraptosis and mitochondrial-mediated apoptosis, and the pathological processes underlying AD, remain elusive. In the present study, the β-amyloid precursor protein gene, and the gene mutations PS1M146L and L286V, were transfected to an SH-SY5Y cell line to establish an AD cell model. Subsequently, an MTT assay was used to examine the cell viability of the AD cell model, while a TUNEL assay was employed to observe the number of positively stained apoptotic cells. Cytoplasmic vacuolization was examined using light microscopy and images were photographed. Furthermore, western blot analysis was utilized to detect the expression of golden biomarkers of the mitochondrial pathway, including Bcl-2 and Bax. The paraptosis inhibitor, cycloheximide, was selected to treat the AD model cells in order to observe the association between paraptosis and mitochondrial-mediated apoptosis. The results indicated that the decrease in the cell viability of the AD cells was initiated at 24 h, as compared with the normal cells (P<0.05). TUNEL-positive stained cells were observed at 48 h, which was later compared with the cell death initiation. In addition, examination of cytoplasmic vacuolization using microscopy indicated that there were a small number of paraptosis cells present at 24 h. The expression levels of Bcl-2 was significantly decreased, while Bax was significantly increased at 48 h. Furthermore, cycloheximide treatment was demonstrated to significantly increase Bcl-2 expression, while decreasing Bax expression (P>0.05). In conclusion, the occurrence of paraptosis was demonstrated in the early pathological stages of AD, which may subsequently damage the mitochondria and trigger mitochondrial pathway-mediated apoptosis. Thus, paraptosis may trigger programmed cell death directly, or indirectly through the regulation of Bcl-2 and Bax protein expression.

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A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells

Cited by 115 publications

References 42 publications

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Inhibition of Protein Degradation Induces Apoptosis through a Microtubule-Associated Protein 1 Light Chain 3-Mediated Activation of Caspase-8 at Intracellular Membranes

Paraptosis triggers mitochondrial pathway-mediated apoptosis in Alzheimer's disease

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