Endoplasmic reticulum targeted Bcl2 confers long term cell survival through phosphorylation of heat shock protein 27

Chandrika, Bhavya Balan; Maney, Sathish Kumar; Lekshmi, Swathi U.; Retnabhai, Santhoshkumar Thankayyan

doi:10.1016/j.biocel.2010.08.011

Cited by 4 publications

(2 citation statements)

References 32 publications

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“…These results hint that Bcl-2 associated with ER can confer resistance against PAC-1-mediated apoptosis, which proceeds via the mitochondria as reported in our previous report. 21 …”

Section: Resultsmentioning

confidence: 99%

ERO1α-dependent endoplasmic reticulum–mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1)

et al. 2013

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Procaspase-activating compound-1 (PAC-1) is the first direct caspase-activating compound discovered; using an in vitro cell-free system of caspase activation. Subsequently, this compound was shown to induce apoptosis in a variety of cancer cells with promising in vivo antitumor activity in canine lymphoma model. Recently, we have reported its ability to kill drug-resistant, Bcl-2/Bcl-xL overexpressing and Bax/Bak-deficient cells despite the essential requirement of mitochondrial cytochrome c (cyt. c) release for caspase activation, indicating that the key molecular targets of PAC-1 in cancer cells are yet to be identified. Here, we have identified Ero1α-dependent endoplasmic reticulum (ER) calcium leakage to mitochondria through mitochondria-associated ER membranes (MAM) and ER luminal hyper-oxidation as the critical events of PAC-1-mediated cell death. PAC-1 treatment upregulated Ero1α in multiple cell lines, whereas silencing of Ero1α significantly inhibited calcium release from ER and cell death. Loss of ER calcium and hyper-oxidation of ER lumen by Ero1α collectively triggered ER stress. Upregulation of GRP78 and splicing of X-box-binding protein 1 (XBP1) mRNA in multiple cancer cells suggested ER stress as the general event triggered by PAC-1. XBP1 mRNA splicing and GRP78 upregulation confirmed ER stress even in Bax/Bak double knockout and PAC-1-resistant Apaf-1-knockout cells, indicating an induction of ER stress-mediated mitochondrial apoptosis by PAC-1. Furthermore, we identified BH3-only protein p53 upregulated modulator of apoptosis (PUMA) as the key molecular link that orchestrates overwhelmed ER stress to mitochondria-mediated apoptosis, involving mitochondrial reactive oxygen species, in a p53-independent manner. Silencing of PUMA in cancer cells effectively reduced cyt. c release and cell death by PAC-1.

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“…These results hint that Bcl-2 associated with ER can confer resistance against PAC-1-mediated apoptosis, which proceeds via the mitochondria as reported in our previous report. 21 …”

Section: Resultsmentioning

confidence: 99%

ERO1α-dependent endoplasmic reticulum–mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1)

et al. 2013

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“…In addition to these ER chaperone proteins, caspase 12 possesses the capability to activate caspase 9, subsequently initiating ER stress-induced apoptosis (54,55). In the present study, CORT activated caspases via excessive ER stress cleaving procaspase into active caspase 9, which in turn activated downstream caspase-cleavage, leading to apoptosis (56).…”

Section: Discussionmentioning

confidence: 69%

Neuroprotective effect of polysaccharides from Gastrodia elata blume against corticosterone‑induced apoptosis in PC12 cells via inhibition of the endoplasmic reticulum stress‑mediated pathway

et al. 2017

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Depression is a common mental health disorder and is the leading cause of disability worldwide. Gastrodia elata (G. elata) was demonstrated to exhibit a neuroprotective effect in the authors' previous study. The present study investigated the effect of polysaccharides from G. elata (GEP) on PC12 cell apoptosis induced by corticosterone (CORT) and its possible underlying mechanisms. PC12 cells were treated with 200 µM CORT in the absence or presence of different concentrations of GEP for 48 h. Then, cell viability was measured by CCK‑8 assay. The lactate dehydrogenase (LDH) leakage was quantified using an LDH assay kit. The apoptosis degree of the PC12 cells and the morphology was measured by DAPI staining. Subsequently, intracellular ROS level was detected by using DCFH‑DA method, the morphology staining of the endoplasmic reticulum in PC12 cells was determined using the cationic probe, and levels of five proteins involved in apoptosis, i.e., glucose‑regulated protein, 78k Da (GRP78), X‑box binding protein 1 (XBP‑1), growth arrest‑ and DNA damage‑inducible gene 153 (GADD153), caspase 9 and caspase 12 were determined by western blotting. The results demonstrated that treatment with 1,000 µg/ml GEP prior to 200 µM CORT exposure significantly protected the PC12 cells from CORT‑induced cell apoptosis, and reduced levels of LDH leakage and intracellular reactive oxygen species. In addition, pretreatment with GEP inhibited the activation of GRP78, X‑BP‑1, GADD153, caspase 9 and caspase 12. These findings suggested that GEP exhibited a neuroprotective effect against CORT‑induced apoptosis in PC12 cells, and the underlying molecular mechanisms were dependent on inhibition of the endoplasmic reticulum stress‑mediated pathway. This provides novel insight into the effect of GEP when used for the treatment of diseases of the nervous system.

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Hsp27 Phosphorylation Patterns and Cellular Consequences

Moens

Kostenko

2012

Heat Shock Proteins

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Endoplasmic reticulum targeted Bcl2 confers long term cell survival through phosphorylation of heat shock protein 27

Cited by 4 publications

References 32 publications

ERO1α-dependent endoplasmic reticulum–mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1)

ERO1α-dependent endoplasmic reticulum–mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1)

Neuroprotective effect of polysaccharides from Gastrodia elata blume against corticosterone‑induced apoptosis in PC12 cells via inhibition of the endoplasmic reticulum stress‑mediated pathway

Hsp27 Phosphorylation Patterns and Cellular Consequences

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