scholarly journals Nanosecond Pulsed Electric Fields Induce Endoplasmic Reticulum Stress Accompanied by Immunogenic Cell Death in Murine Models of Lymphoma and Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2034 ◽  
Author(s):  
Alessandra Rossi ◽  
Olga N. Pakhomova ◽  
Peter A. Mollica ◽  
Maura Casciola ◽  
Uma Mangalanathan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cell Lines ◽  
Electric Fields ◽  
Pulsed Electric Fields ◽  
Immunogenic Cell Death ◽  
Cancer Cell Death ◽  
Cell Plasma ◽  
Nanosecond Pulsed Electric Fields

Depending on the initiating stimulus, cancer cell death can be immunogenic or non-immunogenic. Inducers of immunogenic cell death (ICD) rely on endoplasmic reticulum (ER) stress for the trafficking of danger signals such as calreticulin (CRT) and ATP. We found that nanosecond pulsed electric fields (nsPEF), an emerging new modality for tumor ablation, cause the activation of the ER-resident stress sensor PERK in both CT-26 colon carcinoma and EL-4 lymphoma cells. PERK activation correlates with sustained CRT exposure on the cell plasma membrane and apoptosis induction in both nsPEF-treated cell lines. Our results show that, in CT-26 cells, the activity of caspase-3/7 was increased fourteen-fold as compared with four-fold in EL-4 cells. Moreover, while nsPEF treatments induced the release of the ICD hallmark HMGB1 in both cell lines, extracellular ATP was detected only in CT-26. Finally, in vaccination assays, CT-26 cells treated with nsPEF or doxorubicin equally impaired the growth of tumors at challenge sites eliciting a protective anticancer immune response in 78% and 80% of the animals, respectively. As compared to CT-26, both nsPEF- and mitoxantrone-treated EL-4 cells had a less pronounced effect and protected 50% and 20% of the animals, respectively. These results support our conclusion that nsPEF induce ER stress, accompanied by bona fide ICD.

γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death

2015 ◽  
Vol 93 (4) ◽  
pp. 306-320 ◽  
Author(s):  
Roshan V. Tiwari ◽  
Parash Parajuli ◽  
Paul W. Sylvester
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cell ◽  
Human Breast Cancer ◽  
Beclin 1 ◽  
Time Dependent ◽  
Human Breast ◽  
Cancer Cell Death

The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.

Cell Death Induced by Nanosecond Pulsed Electric Fields and its Dependence on Pulse Duration

2018 ◽  
Vol 101 (3) ◽  
pp. 38-48 ◽  
Author(s):  
RYUYA ADACHI ◽  
SHOTA HATAYAMA ◽  
NOBUAKI OHNISHI ◽  
SUNAO KATSUKI ◽  
TOSHIAKI WADA ◽  
...  
Keyword(s):  
Cell Death ◽  
Pulse Duration ◽  
Electric Fields ◽  
Pulsed Electric Fields ◽  
Nanosecond Pulsed Electric Fields

Cell Death induced by Nanosecond Pulsed Electric Fields and its Dependence on Pulse Duration

2017 ◽  
Vol 137 (6) ◽  
pp. 320-327
Author(s):  
Ryuta Andachi ◽  
Shota Hatayama ◽  
Nobuaki Ohnishi ◽  
Sunao Katsuki ◽  
Toshiaki Wada ◽  
...  
Keyword(s):  
Cell Death ◽  
Pulse Duration ◽  
Electric Fields ◽  
Pulsed Electric Fields ◽  
Nanosecond Pulsed Electric Fields

scholarly journals Towards Solid Tumor Treatment by Nanosecond Pulsed Electric Fields

2009 ◽  
Vol 8 (4) ◽  
pp. 289-306 ◽  
Author(s):  
Axel T. Esser ◽  
Kyle C. Smith ◽  
T. R. Gowrishankar ◽  
James C. Weaver
Keyword(s):  
Cell Death ◽  
Electric Field ◽  
Spatial Scale ◽  
Electric Fields ◽  
Solid Tumor ◽  
Irreversible Electroporation ◽  
Pulsed Electric Fields ◽  
Underlying Mechanism ◽  
Tumor Ablation ◽  
Nanosecond Pulsed Electric Fields

Local and drug-free solid tumor ablation by large nanosecond pulsed electric fields leads to supra-electroporation of all cellular membranes and has been observed to trigger nonthermal cell death by apoptosis. To establish pore-based effects as the underlying mechanism inducing apoptosis, we use a multicellular system model (spatial scale 100 μm) that has irregularly shaped liver cells and a multiscale liver tissue model (spatial scale 200 mm). Pore histograms for the multicellular model demonstrate the presence of only nanometer-sized pores due to nanosecond electric field pulses. The number of pores in the plasma membrane is such that the average tissue conductance during nanosecond electric field pulses is even higher than for longer irreversible electroporation pulses. It is shown, however, that these nanometer-sized pores, although numerous, only significantly change the permeability of the cellular membranes to small ions, but not to larger molecules. Tumor ablation by nanosecond pulsed electric fields causes small to moderate temperature increases. Thus, the underlying mechanism(s) that trigger cell death by apoptosis must be non-thermal electrical interactions, presumably leading to different ionic and molecular transport than for much longer irreversible electroporation pulses.

scholarly journals Interplay between Endoplasmic Reticulum (ER) Stress and Autophagy Induces Mutant p53H273 Degradation

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 392 ◽  
Author(s):  
Alessia Garufi ◽  
Giulia Federici ◽  
Maria Saveria Gilardini Montani ◽  
Alessandra Crispini ◽  
Mara Cirone ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Zinc Supplementation ◽  
Zinc Ion ◽  
Misfolded Proteins ◽  
Missense Mutations ◽  
Chemical Chaperone ◽  
Cancer Cell Death ◽  
The Unfolded Protein Response

The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins in order to survive bioenergetic stress and/or induce cell death. Oncosuppressor TP53 may undergo inactivation following missense mutations within the DNA-binding domain (DBD), and mutant p53 (mutp53) proteins may acquire a misfolded conformation, often due to the loss of the DBD-bound zinc ion, leading to accumulation of hyperstable mutp53 proteins that correlates with more aggressive tumors, resistance to therapies, and poorer outcomes. We previously showed that zinc supplementation induces mutp53 protein degradation by autophagy. Here, we show that mutp53 (i.e., Arg273) degradation following zinc supplementation is correlated with activation of ER stress and of the IRE1α/XBPI arm of the UPR. ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components.

Sign in / Sign up

Export Citation Format

Share Document