scholarly journals Arylquin 1, a potent Par-4 secretagogue, induces lysosomal membrane permeabilization-mediated non-apoptotic cell death in cancer cells

2019 ◽  
Vol 36 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Kyoung-jin Min ◽  
Sk Abrar Shahriyar ◽  
Taeg Kyu Kwon
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Membrane Permeabilization ◽  
Apoptotic Cell Death ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization

scholarly journals Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3388
Author(s):  
Kyoung-jin Min ◽  
Taeg Kyu Kwon
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Ectopic Expression ◽  
Glioma Cells ◽  
Membrane Permeabilization ◽  
Apoptotic Cell Death ◽  
Lysosomal Membrane ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Lysosomal Membrane Permeabilization

FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from I. sinclairii. Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.

scholarly journals Quinacrine-Induced Autophagy in Ovarian Cancer Triggers Cathepsin-L Mediated Lysosomal/Mitochondrial Membrane Permeabilization and Cell Death

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2004
Author(s):  
Prabhu Thirusangu ◽  
Christopher L. Pathoulas ◽  
Upasana Ray ◽  
Yinan Xiao ◽  
Julie Staub ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Cathepsin L ◽  
Membrane Permeabilization ◽  
Apoptotic Cell Death ◽  
Ovarian Cancer Cells ◽  
Autophagic Flux

We previously reported that the antimalarial compound quinacrine (QC) induces autophagy in ovarian cancer cells. In the current study, we uncovered that QC significantly upregulates cathepsin L (CTSL) but not cathepsin B and D levels, implicating the specific role of CTSL in promoting QC-induced autophagic flux and apoptotic cell death in OC cells. Using a Magic Red® cathepsin L activity assay and LysoTracker red, we discerned that QC-induced CTSL activation promotes lysosomal membrane permeability (LMP) resulting in the release of active CTSL into the cytosol to promote apoptotic cell death. We found that QC-induced LMP and CTSL activation promotes Bid cleavage, mitochondrial outer membrane permeabilization (MOMP), and mitochondrial cytochrome-c release. Genetic (shRNA) and pharmacological (Z-FY(tBU)-DMK) inhibition of CTSL markedly reduces QC-induced autophagy, LMP, MOMP, apoptosis, and cell death; whereas induced overexpression of CTSL in ovarian cancer cell lines has an opposite effect. Using recombinant CTSL, we identified p62/SQSTM1 as a novel substrate of CTSL, suggesting that CTSL promotes QC-induced autophagic flux. CTSL activation is specific to QC-induced autophagy since no CTSL activation is seen in ATG5 knockout cells or with the anti-malarial autophagy-inhibiting drug chloroquine. Importantly, we showed that upregulation of CTSL in QC-treated HeyA8MDR xenografts corresponds with attenuation of p62, upregulation of LC3BII, cytochrome-c, tBid, cleaved PARP, and caspase3. Taken together, the data suggest that QC-induced autophagy and CTSL upregulation promote a positive feedback loop leading to excessive autophagic flux, LMP, and MOMP to promote QC-induced cell death in ovarian cancer cells.

Lysosomal membrane permeabilization as a cell death mechanism in cancer cells

2018 ◽  
Vol 46 (2) ◽  
pp. 207-215 ◽  
Author(s):  
Ana Serrano-Puebla ◽  
Patricia Boya
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Proteolytic Enzymes ◽  
Hydrolytic Enzymes ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Lysosomal Membrane Permeabilization ◽  
Regulated Cell Death ◽  
Cathepsin Activity ◽  
Intracellular Cascades

Lysosomes are acidic organelles that contain hydrolytic enzymes that mediate the intracellular degradation of macromolecules. Damage of these organelles often results in lysosomal membrane permeabilization (LMP) and the release into the cytoplasm of the soluble lysosomal contents, which include proteolytic enzymes of the cathepsin family. This, in turn, activates several intracellular cascades that promote a type of regulated cell death, called lysosome-dependent cell death (LDCD). LDCD can be inhibited by pharmacological or genetic blockade of cathepsin activity, or by protecting the lysosomal membrane, thereby stabilizing the organelle. Lysosomal alterations are common in cancer cells and may increase the sensitivity of these cells to agents that promote LMP. In this review, we summarize recent findings supporting the use of LDCD as a means of killing cancer cells.

scholarly journals Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1621
Author(s):  
Jennifer Beauvarlet ◽  
Rabindra Nath Das ◽  
Karla Alvarez-Valadez ◽  
Isabelle Martins ◽  
Alexandra Muller ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Membrane Damage ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Cancer Therapies ◽  
Quadruplex Dna ◽  
Lysosomal Membrane Permeabilization ◽  
G Quadruplex ◽  
Massive Cell Death

Lysosomes play a key role in regulating cell death in response to cancer therapies, yet little is known on the possible role of lysosomes in the therapeutic efficacy of G-quadruplex DNA ligands (G4L) in cancer cells. Here, we investigate the relationship between the modulation of lysosomal membrane damage and the degree to which cancer cells respond to the cytotoxic effects of G-quadruplex ligands belonging to the triarylpyridine family. Our results reveal that the lead compound of this family, 20A promotes the enlargement of the lysosome compartment as well as the induction of lysosome-relevant mRNAs. Interestingly, the combination of 20A and chloroquine (an inhibitor of lysosomal functions) led to a significant induction of lysosomal membrane permeabilization coupled to massive cell death. Similar effects were observed when chloroquine was added to three new triarylpyridine derivatives. Our findings thus uncover the lysosomal effects of triarylpyridines compounds and delineate a rationale for combining these compounds with chloroquine to increase their anticancer effects.

scholarly journals Natural Products Induce Lysosomal Membrane Permeabilization as an Anticancer Strategy

Medicines ◽  
2021 ◽  
Vol 8 (11) ◽  
pp. 69
Author(s):  
Reginald Halaby
Keyword(s):  
Cell Death ◽  
Natural Products ◽  
Global Health ◽  
Cancer Cells ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Economic Issue ◽  
Neoplastic Cells ◽  
Lysosomal Membrane Permeabilization ◽  
Dividing Cells

Cancer is a global health and economic issue. The majority of anticancer therapies become ineffective due to frequent genomic turnover and chemoresistance. Furthermore, chemotherapy and radiation are non-specific, killing all rapidly dividing cells including healthy cells. In this review, we examine the ability of some natural products to induce lysosomal-mediated cell death in neoplastic cells as a way to kill them more specifically than conventional therapies. This list is by no means exhaustive. We postulate mechanisms to explain lysosomal membrane permeabilization and its role in triggering cell death in cancer cells.

scholarly journals Chloroquine induces lysosomal membrane permeability mediated apoptotic cell death in bladder cancer cells

2016 ◽  
Vol 27 (2) ◽  
pp. S5 ◽  
Author(s):  
Hung-En Chen ◽  
Ji-Fan Lin ◽  
Te-Fu Tsai ◽  
Yi-Chia Lin ◽  
Kuang-Yu Chou ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Membrane Permeability ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Lysosomal Membrane ◽  
Bladder Cancer Cells

scholarly journals Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells

2015 ◽  
Vol 59 (2) ◽  
pp. 178-189 ◽  
Author(s):  
Raquel Ordoñez ◽  
Anna Fernández ◽  
Néstor Prieto-Domínguez ◽  
Laura Martínez ◽  
Carmen García-Ruiz ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Liver Cancer Cells
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